JP6366150B2 - E-selectin antagonist compounds, compositions and methods of use - Google Patents

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is filed under US Provisional Application No. 61 / 579,646, filed Jan. 5, 2012, filed Dec. 22, 2011 under US Patent Act §119 (E). US Provisional Application No. 61 / 583,547, US Provisional Application No. 61 / 704,399 filed on September 21, 2012, and US Provisional Application No. 61 / filed on September 21, 2012. 704,424 (these applications are hereby incorporated by reference in their entirety).

TECHNICAL FIELD Agents and compositions thereof that are E-selectin antagonists and can be used as therapeutic agents are described herein. Described herein are methods and uses for these E-selectin antagonists for treating and preventing diseases, disorders, and symptoms associated with E-selectin activity.

2. Description of Related Fields Many pathological conditions such as autoimmune and inflammatory diseases, shock, and reperfusion injury involve abnormal adhesion of leukocytes. Abnormal adhesion of selectin-mediated cell adhesion can result in tissue damage instead of repair. Selectins include three cell adhesion molecules that have been well characterized for their role in leukocyte homing. E-selectin (endothelial selectin) and P-selectin (platelet selectin) are expressed by endothelial cells at the site of inflammation or injury. Recent studies suggest that cancer cells are immunostimulatory and interact with selectins to migrate and metastasize (eg, Gout et al., Clin. Exp. Metastasis 25: 335-344 (2008)). Kannagi et al., Cancer Sci. 95: 377-84 (2004); Witz, Immunol. Lett. 104: 89-93 (2006); Brodt et al., Int. J. Cancer 71: 612-19 (1997); about).

  Some cancers are sufficiently treatable if they are treated before the cancer has moved outside the primary site. However, in many cases, when the cancer has spread beyond the primary site, treatment options are limited and survival statistics are dramatically reduced. For example, if colorectal cancer is detected at a local stage (ie, limited to the colon or rectum), more than 90% of the diagnosed will survive for more than 5 years. Conversely, when colorectal cancer has spread to distant sites (ie, metastasized from the primary site to the distant site), the 5-year survival rate of the subject is dramatically reduced to only 11%.

  According to the estimated incidence in 2012, the most common types of cancer are prostate cancer, breast cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, non-Hodgkin lymphoma, kidney cancer, thyroid cancer, leukemia, uterus Examples include intimal cancer and pancreatic cancer. The cancer with the highest expected incidence is prostate cancer, and more than 240,000 new cases are expected in the United States in 2012, with the lowest expected incidence being pancreatic cancer, about 44,000 in 2012. New cases are expected.

  The highest mortality rate is in patients with lung cancer. In 2012, over 160,000 patients are expected to succumb to the disease. Despite significant investments in financial and human resources, cancers such as colorectal cancer remain one of the leading causes of death. In the United States, colorectal cancer is the second most common cancer-related cause of death in cancers that affect both men and women. Over the past few years, more than 50,000 colorectal cancer patients die each year.

  The four most common hematological cancers are acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). Adults with leukemia and other cancers of the blood, bone marrow and lymphatic system are ten times more likely than children; however, leukemia is the most common childhood cancer, with 75% of childhood leukemias being ALL. AML is the most common adult leukemia. About 47,000 new cases are diagnosed each year, and about 23,500 people die each year from leukemia.

  Cancer therapeutic drugs can contribute to endothelial injury, which then causes venous thromboembolism (VTE). Other risk factors that make an individual susceptible to VTE include congestion or endothelial injury (eg, due to indwelling venous devices; major trauma or injury), medical symptoms (eg, malignancy, pregnancy, cardiovascular symptoms) Or events), administration of other drugs such as hormones, and thrombus formation propensity. A blockage of blood flow in the body takes oxygen away from the tissue, resulting in tissue damage, destruction, or death. Thrombus and embolism can remain in the blood vessel and block blood flow. In the United States, approximately 900,000 VTE cases (including deep vein thrombosis (DVT) and pulmonary embolism (PE)) are diagnosed each year, and approximately 300,000 cases are fatal (Heit et al., Blood 2005; 106 (abstract)). When erythrocytes and fibrin and, to a lesser extent, platelets and leukocytes form a mass in an intact vein, a venous thrombus occurs. Typically, pulmonary embolism occurs when a thrombus or thrombotic protein remains in the pulmonary artery away from the vein wall. Since the signs and symptoms of VTE are non-specific and difficult to diagnose, the exact incidence of VTE is unknown, but the annual incidence can be 0.1-0.2% (eg, Anderson et al. Arch) Intern. Med. 151: 933-38 (1991); see Silverstein et al., Arch. Intern. Med. 158: 585-93 (1998)).

Gout et al., Clin. Exp. Metastasis (2008) 25: 335-344 Kannagi et al., Cancer Sci. (2004) 95: 377-84 Witz, Immunol. Lett. (2006) 104: 89-93 Brodt et al., Int. J. et al. Cancer (1997) 71: 612-19

BRIEF SUMMARY Briefly, provided herein are agents that are E-selectin antagonists, compositions comprising the agents, and methods of using the agents. These agents treat and prevent diseases and disorders that can be treated by inhibiting the binding of E-selectin to an E-selectin ligand, such as cancer, metastasis, and thrombosis among those described herein. Useful for. In certain embodiments, glycomimetic compounds that are E-selectin antagonists are provided. The following embodiments are disclosed herein.

  In one embodiment, a compound having the following formula (I) (which is a sugar mimetic compound):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each have the definition described herein), or a pharmaceutically acceptable thereof Salts, isomers, tautomers, hydrates, or solvates are provided herein.

In certain embodiments,
R ¹ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C ₈ haloalkynyl;
R ² is H, or a non-sugar mimetic moiety or a linker-non-sugar mimetic moiety, wherein the non-sugar mimetic moiety is polyethylene glycol, thiazolyl, chromenyl, —C (═O) NH (CH ₂ ) _{1 -4} NH _{2, C} 1 -C ₈ alkyl, and -C (= O) OY (wherein, Y _is, C 1 -C _{4 alkyl,} a C 2 -C ₄ alkenyl or _C 2 -C ₄ alkynyl) Selected from;
R ³ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl, C ₂ -C ₈ haloalkynyl or cyclopropyl Is;
R ⁴ is —OH or —NZ ¹ Z ² (wherein Z ¹ and Z ² are each independently H, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C ₈ haloalkynyl, or Z ¹ and Z ² combine to form a ring);
R ⁵ is C ₃ -C ₈ cycloalkyl;
R ⁶ is —OH, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C ₈ haloalkynyl. Is;
R ⁷ is —CH ₂ OH, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C _8. Haloalkynyl; and R ⁸ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C. ₈ haloalkynyl.

  For example, further substructures comprising compounds of formula (Ia), as well as other substructures and specific structures of sugar mimetic compounds of formula (I) are described in more detail herein. Also provided are pharmaceutical compositions comprising any one or more of the compounds described above and herein and a pharmaceutically acceptable excipient.

  A method for treating or preventing metastasis of cancer cells in a subject, comprising a structure of formula (I), a substructure (Ia), or any other substructure described herein or specific Provided herein is a method comprising administering a compound having a structure to the subject, or administering a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.

  In another embodiment, a method for treating or preventing cancer cell metastasis in a subject comprising: (a) a pharmaceutically acceptable excipient; and (b) binding to E-selectin with a formula An agent capable of competing with a compound having the structure of (I), substructure (Ia), or any other substructure or specific structure described herein, comprising an antibody, a polypeptide, There is provided a method comprising administering to the subject a pharmaceutical composition comprising an agent that is a peptide or aptamer.

  In yet another embodiment, a method for inhibiting cancer cells from infiltrating the bone marrow in a subject, comprising a structure of formula (I), substructure (Ia), or any of those described herein A method comprising administering to the subject a compound having any other substructure or specific structure of or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient. Provided.

  In another embodiment, a method for inhibiting cancer cells from infiltrating the bone marrow in a subject comprising (a) a pharmaceutically acceptable excipient and (b) binding to E-selectin. An agent capable of competing with a compound having the structure of formula (I), substructure (Ia), or any other substructure or specific structure described herein, comprising: There is provided a method comprising administering to the subject a pharmaceutical composition comprising an agent that is a peptide, peptide, or aptamer.

  In one embodiment, a method for inhibiting tumor cells expressing an E-selectin ligand from adhering to endothelial cells expressing E-selectin comprising the structure of formula (I), Contact with a compound having substructure (Ia), or any other substructure or specific structure described herein, or comprising said compound and a pharmaceutically acceptable excipient Administering a pharmaceutical composition to allow said compound to interact with E-selectin present on said endothelial cells, thereby inhibiting the binding of said tumor cells to said endothelial cells Is provided. In a specific embodiment, said endothelial cells are present in the bone marrow.

  In another embodiment, a method for treating cancer in a subject comprising (a) a structure of formula (I), a substructure (Ia), or any other substructure described herein. Or administering a compound having a specific structure to the subject, or administering a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient, and (b) (i) chemistry There is provided a method comprising performing at least one of therapy and (ii) radiation therapy on said subject.

  In yet another embodiment, a method for treating or preventing thrombosis in a subject, comprising a structure of formula (I), substructure (Ia), or any other subordinate described herein There is provided a method comprising administering to the subject a compound having a structure or a specific structure, or administering a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.

  In yet another embodiment, a method for treating or preventing thrombosis in a subject comprising (a) a pharmaceutically acceptable excipient and (b) binding to E-selectin with the formula ( An agent capable of competing with a compound having the structure of I), substructure (Ia), or any other substructure or specific structure described herein, wherein the antibody, polypeptide, peptide Or a pharmaceutical composition comprising a pharmaceutical composition comprising an agent that is an aptamer is provided.

  In one embodiment, a method for enhancing the survival of hematopoietic stem cells in a subject comprising the structure of formula (I), substructure (Ia), or any other substructure described herein, or There is provided a method comprising administering to the subject a compound having a specific structure, or administering a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. In yet another embodiment, a method for enhancing the survival of hematopoietic stem cells in a subject comprising (a) a pharmaceutically acceptable excipient and (b) binding to E-selectin with the formula ( An agent capable of competing with a compound having the structure of I), substructure (Ia), or any other substructure or specific structure described herein, wherein the antibody, polypeptide, peptide Or a pharmaceutical composition comprising an agent that is an aptamer is provided to the subject. In certain embodiments, the subject has received or will receive chemotherapy or radiation therapy or both chemotherapy and radiation therapy.

  In the manufacture of a medicament for treating or preventing metastasis of cancer cells, having the structure of formula (I), substructure (Ia), or any other substructure or specific structure described herein The use of compounds is also provided herein.

  In another embodiment, the structure of formula (I), substructure (Ia), in the manufacture of a medicament for use in treating cancer in combination with chemotherapy or radiation therapy or both chemotherapy and radiation therapy, Or provided herein is the use of a compound having any other substructure or specific structure described herein.

  In another embodiment, in the manufacture of a medicament for treating or preventing thrombosis, a structure of formula (I), a substructure (Ia), or any other substructure or specification described herein The use of a compound having a unique structure is provided herein.

  In yet another embodiment, in the manufacture of a medicament for inhibiting cancer cells from infiltrating the bone marrow, the structure of formula (I), substructure (Ia), or any other described herein The use of compounds having substructures or specific structures is provided herein.

  In yet another embodiment, the structure of formula (I), substructure (in the manufacture of a medicament for inhibiting tumor cells expressing an E-selectin ligand from adhering to endothelial cells expressing E-selectin, Provided herein is the use of a compound having Ia), or any other substructure or specific structure described herein.

  In another embodiment, in the manufacture of a medicament for enhancing the survival of hematopoietic stem cells, the structure of formula (I), the substructure (Ia), or any other substructure or specification described herein The use of a compound having a unique structure is provided herein.

  In another embodiment, a method for treating or preventing (ie, reducing or reducing the likelihood of developing) cancer cell metastasis in an individual (ie, a subject) in need of treatment or prevention of cancer cell metastasis. And a method comprising administering to said individual one or more of the sugar mimetic compounds of formula (I) described above and herein, or a pharmaceutical composition comprising said compound. .

In yet another embodiment, a method for reducing the likelihood of cancer cell metastasis in an individual in need of reducing the likelihood of cancer cell metastasis, comprising the above and Provided is a method comprising administering to said individual an agent that competes with a compound of formula (I) described herein, which is an antibody, polypeptide, peptide, or aptamer. In certain embodiments, the agent is in combination with a pharmaceutically acceptable excipient (ie, a pharmaceutical composition).

  In yet another embodiment, a method for reducing the likelihood of cancer cell bone marrow invasion in an individual in need of reducing the likelihood of cancer cell bone marrow infiltration comprising the above and the present There is provided a method comprising administering to said individual any one or more of the sugar mimetic compounds of formula (I) described herein, or a pharmaceutical composition comprising said compound.

  In another embodiment, a method for reducing the likelihood of cancer cell infiltration into the bone marrow in an individual in need of reducing the likelihood of cancer cell infiltration into the bone marrow, wherein the method is directed against E-selectin. An agent that competes (ie is capable of competing) with a compound of formula (I) described above and herein for binding, wherein the agent is an antibody, polypeptide, peptide, or aptamer. Are provided. In certain embodiments, the agent is in combination with a pharmaceutically acceptable excipient (ie, a pharmaceutical composition).

  In yet another embodiment, a method for reducing the likelihood of thrombus formation in an individual, comprising any one or more of the sugar mimetic compounds described above and herein, or a medicament comprising said compound A method is provided comprising administering a composition to the individual. In other specific embodiments, a method for reducing the likelihood of thrombus formation in an individual that competes with a compound described above and herein for binding to E-selectin (ie, competition). There is provided a method comprising administering to the individual any one or more of an agent that can be an antibody, a polypeptide, a peptide, or an aptamer.

  In the following description, various embodiments are set forth in some detail for a thorough understanding. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the embodiments. The term “comprise” and its endings (“comprises” and “comprising” are used throughout this specification and the following claims, unless the context requires otherwise. ) "Etc.) should be interpreted in a non-limiting inclusive sense, i.e." including but not limited to ". In addition, the term “comprising” (and “comprises” or “comprises” or “having” or “including” and the like Terminology) in certain other specific embodiments, eg, any material composition, composition, method or process described herein is characterized by “consisting of” the described feature It is not intended to exclude that it may be, or may be “consisting essentially of” the features described. The headings provided herein are for convenience and do not explain the scope or meaning of the embodiments recited in the claims.

  Throughout this specification, reference to “in one embodiment” or “in an embodiment” means that the particular property, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment. To do. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places in the specification are not necessarily all referring to the same embodiment. Further, in one or more embodiments, particular properties, structures, or features can be combined in any suitable manner.

Also, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include the plural unless the context clearly indicates otherwise. Thus, for example, a reference to “a compound” can refer to one or more compounds or a plurality of such compounds, and a reference to “a cell” or “the cell” refers to one or more cells and one of ordinary skill in the art. References to known equivalents thereof (eg, a plurality of cells) and the like are included. Similarly, a reference to “composition” includes a plurality of such compositions and refers to one or more compositions unless the context clearly indicates otherwise. If a method step is described in the description or claims and is described as occurring in a particular order, the first step is “prior to” the second step (ie, before The description “occurs (or is performed)” has the same meaning as described for the situation where the second step occurs (or is performed) “following” the first step. When the term “about” refers to a numerical or numerical range, the numerical or numerical range referred to is an approximation within that of the experimental variation (or within the statistical experimental error), and therefore the numerical Or it means that the numerical range can vary from 1% to 15% of the indicated numerical range or numerical range. It should also be noted that the term “or” is generally employed in its meaning (including “and / or”) unless the context clearly indicates otherwise. The term “at least one” has the same meaning or understanding as the term “one or more” when referring to at least one compound or at least one composition, for example.

  These and other aspects of the invention will be apparent upon reference to the following detailed description and attached drawings. All references disclosed herein are hereby incorporated by reference in their entirety as if each was individually incorporated.

FIG. 1 (FIG. 1A, FIG. 1B, FIG. 1C and FIG. 1D) is a diagram illustrating the synthesis of an embodiment of the compound having Formula I (Compound 25) provided herein. FIG. 1 (FIG. 1A, FIG. 1B, FIG. 1C and FIG. 1D) is a diagram illustrating the synthesis of an embodiment of the compound having Formula I (Compound 25) provided herein. FIG. 1 (FIG. 1A, FIG. 1B, FIG. 1C and FIG. 1D) is a diagram illustrating the synthesis of an embodiment of the compound having Formula I (Compound 25) provided herein. FIG. 1 (FIG. 1A, FIG. 1B, FIG. 1C and FIG. 1D) is a diagram illustrating the synthesis of an embodiment of the compound having Formula I (Compound 25) provided herein. FIG. 2 is a diagram illustrating the synthesis of an embodiment of a compound having Formula I provided herein. FIG. 3 is a diagram illustrating that E-selectin plays a central role in cancer progression. FIG. 4 compares the effect of compound 25 (“Cmpd.25”) of FIG. 1 vs. low molecular weight heparin (“LMW heparin”) on the weight of a thrombus formed 2 days after EIM (electrolytic vena cava model) injury. It is a graph which shows a result. “Non-treatment” represents the weight of the thrombus 2 days after EIM injury. “Control” (saline) represents a venous explant without injury. “Sham” represents a venous explant two days after electrode implantation in the absence of current. Compound 25 vs. untreated, P = 0.0271; LMW heparin vs. untreated, P = 0.0203. FIG. 5 is a graph showing a comparison of the effect of compound 25 (“Cmpd.25”) versus low molecular weight heparin (“LMWH”) on the time required for clot formation.

DETAILED DESCRIPTION Provided herein are agents that inhibit the binding of E-selectin to an E-selectin ligand. The agent includes a sugar mimetic compound described herein that inhibits the interaction of E-selectin with sialyl Le ^a (sLe ^a ) or sialyl Le ^x (sLe ^x ). Drugs that are antibodies, polypeptides, peptides, and aptamers that bind to or near the binding site on E-selectin to which the compound binds (ie, compete with the compound to form E
-Also provided are antibodies, polypeptides, peptides, or aptamers described herein that are capable of inhibiting the interaction of selectins with sialyl Le ^a (sLe ^a ) or sialyl Le ^x (sLe ^x ).

  The E-selectin antagonists described herein are those that bind E-selectin to an E-selectin ligand (which, for example, promotes inflammatory responses, tumor cell migration (ie, promotes or enhances metastasis), tumor cells, For the treatment of diseases or disorders associated with, mediated by or exacerbated by undesirable biological activity including increased chemoresistance and contribution to thrombus formation May be used in the method. In certain embodiments, an agent comprising an E-selectin antagonist glycomimetic compound described herein may be used in the treatment of cancer in combination with chemotherapy, radiation therapy, or both. In yet other embodiments, the compounds described herein inhibit cancer cells from infiltrating the bone marrow and reduce the adhesion of tumor cells to endothelial cells, including cells in the bone marrow. May be used to treat and prevent metastasis of cancer cells (also referred to herein as tumor cells), including or inhibiting.

  Provided herein are agents that significantly inhibit venous thromboembolism in a treatment model of thrombus formation and that have certain advantages over current thrombosis treatments, such as glycomimetic compounds. Thus, the agents described herein can treat and prevent thrombosis, including deep vein thrombosis and associated pulmonary embolism (ie, its development in a statistically, biologically or clinically significant manner) Can be used to reduce, inhibit, or reduce sex).

  The E-selectin antagonists described herein (eg, compounds of Formula I) have increased stability because they contain substituents that are less likely to be cleaved by esterases. Accordingly, these compounds provide improved compounds over those previously described in the art.

In one embodiment provided herein, an E-selectin antagonist is a glycomimetic compound having the following formula (I):

Or a pharmaceutically acceptable salt (ie, physiologically relevant salt), isomer, tautomer, hydrate, or solvate thereof. Formula I includes R ^{1 to} R ^8, which may be substituted on a compound where a substituent (eg, R ⁸ ) or a portion of the substituent (eg, R ³ ) can vary according to the selection provided herein. Represents the position.

In one embodiment, R ¹ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C _8. Haloalkynyl;
R ² is H, or a non-sugar mimetic moiety or linker-non-sugar mimetic moiety (ie, a linker attached to a non-sugar mimetic moiety), wherein the non-sugar mimetic moiety is polyethylene glycol, thiazolyl, chromenyl, C ₁ -C ₈ alkyl, —C (═O) NH (CH ₂ ) _1-4 NH ₂ , and —C (═O) OY (where Y is C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl);
R ³ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl, C ₂ -C ₈ haloalkynyl or cyclopropyl Is;
R ⁴ is —OH or —NZ ¹ Z ² (wherein Z ¹ and Z ² are each independently H, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C ₈ haloalkynyl, or Z ¹ and Z ² combine to form a ring);
R ⁵ is C ₃ -C ₈ cycloalkyl;
R ⁶ is —OH, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C ₈ haloalkynyl. Is;
R ⁷ is —CH ₂ OH, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C _8. Haloalkynyl; and R ⁸ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C. ₈ haloalkynyl.

In some embodiments, Compounds of formula (I) ^{is (a) R 1, R 3} , at least one is _C 1 -C ₈ haloalkyl of R 6, ^{R 7} and ^{R 8;} (b) At least one of R ³ , R ⁶ , R ⁷ and R ⁸ is C ₁ -C ₈ haloalkyl; (c) at least two of R ¹ , R ³ , R ⁶ , R ⁷ and R ⁸ are C ₁ -C ₈ or haloalkyl; (d) ^{R 2} is a linker - or a non-sugar mimetic moiety; ^{or, (e) R 1, R} 3, R 6, at least one is _C ^{R 7} and ^{R 8} ₁ —C ₈ haloalkyl, wherein R ² is a linker-non-sugar mimetic moiety.

In certain embodiments of the compound of formula I, C ₁ -C ₈ haloalkyl is —CH ₂ X, —CH ₂ — (CH ₂ ) _m —CH ₂ X, —CHX ₂ , —CH ₂ — (CH ₂ ). _m —CHX ₂ , —CX ₃ and —CH ₂ — (CH ₂ ) _m —CX _{3 wherein} m is 0-6 and X is F, Cl, Br or I. The In this embodiment, the terminal carbon is substituted with one or more halo radicals. In a specific embodiment, X is F. When more than one halo radical is present, each is independently selected. The number of methylene groups represented by “m” is “0-6”, including 0, 1, 2, 3, 4, 5, 6 and between 0-6 and 0-6 All ranges are included. In certain embodiments, at least one of the C ₁ -C ₈ haloalkyl is CH ₂ X, —CHX ₂ or —CX ₃ ; in certain more specific embodiments, X is F.

In one embodiment of the compounds of formula (I), R ¹ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ halo. alkenyl or _C 2 -C ₈ haloalkynyl. In certain embodiments of compounds of formula I, R ¹ is C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl. In a more specific embodiment, R ¹ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl. In more specific embodiments, R ¹ is methyl (—CH ₃ ), ethyl (CH ₂ CH ₃ ), or —CF ₃ or —CHF ₂ . In another embodiment, R ¹ is methyl (—CH ₃ ) or —CHF ₂ .

In one embodiment of the compound of formula (I), R ² is H, or a non-sugar mimetic moiety (M) or a linker (L) -non-sugar mimetic moiety, wherein the non-sugar mimetic moiety is C ₁ -C _{8 alkyl, -C (= O) NH (} CH 2) 1-4 NH 2, polyethylene glycol (PEG), thiazolyl, chromenyl and -C (= O) OY (wherein, Y is, _{C 1} - Selected from C ₄ alkyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl). In one particular embodiment, R ² is a non-sugar mimetic moiety (M), a linker (L) -non-sugar mimetic moiety (also indicated as -L-non-sugar mimetic moiety or -LM), wherein The non-sugar mimetic moiety is polyethylene glycol. In certain embodiments, R ² is —C (═O) NH (CH ₂ ) ₂ NH ₂ . In certain embodiments, when R ² comprises a non-sugar mimetic moiety or linker-non-sugar mimetic moiety as described herein, these moieties have advantageous or improved properties, eg, enhanced Bioavailability; desired pharmacokinetics; improved stability, etc. are provided to compounds and are non-immunogenic. Other exemplary non-sugar mimetic moieties described herein include thiazolyl and chromenyl heteroaryl, such as 4-methylthiazolyl and 7-hydroxy-2H-chromen-2-one-yl. In some embodiments, R ² is H.

R ² may be linked to the glycomimetic moiety of the compound of formula (I), either directly or via a linker (L). Linkers are well known to those skilled in the art. In certain embodiments, the linker linking the sugar mimetic moiety of Formula I to the non-sugar mimetic moiety (M) is —C (═O) NH (CH ₂ ) _1-4 NHC (═O) —; In a specific embodiment, the linker is —C (═O) NH (CH ₂ ) NHC (═O) —, or the linker is —C (═O) NH (CH ₂ ) ₂ NHC (═ O)-. In certain other embodiments, the linker is —C (═O) NH (CH ₂ ) _1-4 NHC (═O) (CH ₂ ) _1-4 ; in more specific embodiments, the linker Is —C (═O) NH (CH ₂ ) NHC (═O) —CH ₂ , or the linker is —C (═O) NH (CH ₂ ) ₂ NHC (═O) — (CH _{2 2} ). Linkers also include those referred to in the art as “click chemistry” linkers (eg, Brik et al., Chem. Bio. Chem. 2003, 4, 1246; Helms et al., J. Am. Chem. Soc. 2004, 126, 15020; Robert et al., Org. Lett. 2003, 5, 1753; see Moses et al., Chem. Soc. Rev 2007, 36, 1249-1262).

  Other exemplary linkers are described in WO 2007/028050. As further examples, linkers include the following.

In still other embodiments, the linker is

It is.

In another embodiment, the linker is —C (═O) —NH— (CH ₂ ) ₂ —NH—; —CH ₂ —NH—CH ₂ — or —C (═O) —NH—CH ₂ —. is there.

In one embodiment of the compound of formula (I), R ³ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl. a _C 2 -C ₈ haloalkynyl, or cyclopropyl. In certain other embodiments of the compound of formula I, R ³ is C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl or cyclopropyl. In more specific embodiments, R ³ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl. In a more specific embodiment, R ³ is —CH ₃ (methyl) or —CH ₂ —CH ₃ (ethyl) or —CF ₃ or —CHF ₂ . In still other embodiments, R ³ is methyl or trifluoromethyl.

In one embodiment of the compound of formula (I), R ⁴ is —OH, or —NZ ¹ Z ² , wherein —Z ¹ and Z ² are each independently H, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C ₈ haloalkynyl, or Z ¹ and Z ² are attached Forming a ring). When Z ¹ and Z ² are combined to form a ring, the ring is a heterocycle in which the heteroatom is N. In one specific embodiment, R ⁴ is —OH or —NZ ¹ Z ² , wherein Z ¹ and Z ² are each H or C ₁ -C ₈ alkyl. In a more specific embodiment, Z ¹ and Z ² are each —CH ₃ and —NZ ¹ Z ² is —N (CH ₃ ) ₂ .

In one embodiment of the compound of formula (I), R ⁵ is C ₃ -C ₈ cycloalkyl (ie, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). In another embodiment, R ⁵ is C ₃ -C ₆ cycloalkyl (ie, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain embodiments of compounds of formula I, R ⁵ is cyclohexyl.

In one embodiment of the compound of formula (I), R ⁶ is —OH, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ —. C ₈ haloalkenyl or C ₂ -C ₈ haloalkynyl. In other specific embodiments of the compound of formula I, R ⁶ is —OH.

In one embodiment of the compounds of formula (I), R ⁷ is —CH ₂ OH, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C is ₂ -C ₈ haloalkenyl or _C 2 -C ₈ haloalkynyl. In another specific embodiment of the compound of formula I, R ⁷ is —CH ₂ OH, C ₁ -C ₈ alkyl, or C ₁ -C ₈ haloalkyl. In more specific embodiments, R ⁷ is —CH ₂ OH or —CH ₃ . In another specific embodiment, R ⁷ is C ₁ -C ₃ haloalkyl. In more specific embodiments, R ⁷ is —CH ₂ F, —CHF ₂ or —CF ₃ . In another specific embodiment, R ⁷ is —CH ₂ OH or —CHF ₂ .

In one embodiment of the compounds of formula (I), R ⁸ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ halo. alkenyl or _C 2 -C ₈ haloalkynyl. In another specific embodiment of the compound of formula I, R ⁸ is C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl. In more specific embodiments, R ⁸ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl. In more specific embodiments, R ⁸ is methyl (—CH ₃ ), —CH ₂ F, —CHF _2, or trifluoromethyl (—CF ₃ ). In another specific embodiment, R ⁸ is methyl or trifluoromethyl (—CF ₃ ).

In certain embodiments of compounds of formula I, at least one or at least two of R ¹ , R ³ , R ⁶ , R ^7, and R ⁸ are C ₁ -C ₈ haloalkyl. In certain other specific embodiments, at least one of R ³ , R ⁶ , R ^7, and R ⁸ is C ₁ -C ₈ haloalkyl. In other specific embodiments, R ² is a linker (L) -non-sugar mimetic moiety (M); in yet other specific embodiments, R ² is a linker (L) -non-sugar mimetic moiety (M M) and at least one of R ¹ , R ³ , R ⁶ , R ⁷ and R ⁸ is C ₁ -C ₈ haloalkyl. When two or more of R ¹ , R ³ , R ⁶ , R ⁷ and R ⁸ are C ₁ -C ₈ haloalkyl, the haloalkyl is independently selected (ie, may be the same or different) Or both (if at least 3 are present)). At least one or more of R ¹ , R ³ , R ⁶ , R ⁷ and R ⁸ is C ₁ -C ₈ haloalkyl, and R ² is a non-sugar mimetic moiety (M) or a linker (L) -non-sugar mimetic moiety ( -LM) may improve the oral bioavailability of the compound and / or increase the half-life of the compound.

In another embodiment of the compounds of formula (I) provided herein, R ⁵ is cyclohexyl, R ⁶ is —OH, and the compound has the following formula (Ia):

Wherein R ¹ is C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl;
R ² is H, or a non-sugar mimetic moiety or a linker-non-sugar mimetic moiety, wherein the non-sugar mimetic moiety is polyethylene glycol, thiazolyl, chromenyl, C ₁ -C ₈ alkyl, —C (═O ) NH (CH ₂ ) _1-4 NH ₂ and —C (═O) OY (wherein Y is C ₁ -C ₄ alkyl);
R ³ is C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, or cyclopropyl; R ⁴ is —OH or —NZ ¹ Z ² , wherein Z ¹ and Z ² are each independently , H or C ₁ -C ₈ alkyl);
R ⁷ is —CH ₂ OH, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, and R ⁸ is C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl), or a pharmaceutical thereof Having a pharmaceutically acceptable salt (ie a physiologically relevant salt), isomer, tautomer, hydrate, or solvate.

In certain embodiments, halo is F. In other specific embodiments, R ¹ is —CH ₃ , —CH ₂ CH ₃ , —CH ₂ F, —CHF ₂ , —CF ₃ , —CH ₂ CH ₂ F, —CH ₂ CHF ₂ , or — CH ₂ CF ₃ . In other embodiments, R ³ is —CH ₃ , —CH ₂ F, —CHF ₂ , or —CF ₃ . In yet another specific embodiment, R ⁴ is —OH or —N (CH ₃ ) ₂ . In certain embodiments, R ⁷ is —CH ₂ OH, —CH ₃ , —CH ₂ F, —CHF ₂ , or —CF ₃ . In yet another specific embodiment, R ⁸ is —CH ₃ , —CH ₂ F, —CHF ₂ , or —CF ₃ .

In certain specific embodiments, R ¹ is ethyl, CF ₃ , or —CHF ₂ ; R ³ is methyl or —CF ₃ ; R ⁴ is —OH, or —N (CH ₃ ) ₂ ; R ⁵ is cyclohexyl; R ⁶ is —OH; R ⁷ is —CH ₂ —OH, —CHF ₂ , or CF ₃ ; R ⁸ is methyl, —CF ₃ Or an —CHF ₂ ; and R ² is H as described above for compounds of formula I, or a non-sugar mimetic moiety or a linker-non-sugar mimetic moiety. The Examples described herein include the following structural formulas:

One of them.

In certain specific embodiments, R ² is H, —C (═O) NH (CH ₂ ) ₂ NH ₂ , or —C (═O) OCH ₃ (also referred to as —COOCH ₃ ). Exemplary compounds have the formula:

One of them.

  The following compounds of formula (I):

Are also provided herein.

In certain embodiments of compounds of formula I and formula Ia, R ² is a non-sugar mimetic moiety that is polyethylene glycol (PEG). PEG is a polymer of repeating ethylene oxide units. Length and hence molecular weight will vary depending on how many repeat units are present. As used herein, ethylene oxide units are

Where n is an integer or a general integer range of 1 to 100 and any similar range within the general range. For example, the integer range of n is 1-25, 1-50, 2-15, 2-20, 2-25, 2-40, 2-50, 2-100, 5-20, 5-40, 5 100 and all other numerical combinations may be used. In certain embodiments, n is 4, 8, 12, 16, 20, 24, or 28.

  In certain embodiments, the following compounds:

PEG is a non-sugar mimetic moiety (M) and the linker (L) is —C (═O) NH (CH ₂ ) to provide one of the formulas, where n is 1-100. ₂ NHC (= O)-. In certain embodiments, n is 4, 8, 12, 16, 20, 24, or 28.

In two particular embodiments where R ² is PEG, the compound of formula I has the following formula:

One of them.

In certain embodiments, R ² is a linker-non-sugar mimetic moiety, wherein the non-sugar mimetic moiety is thiazolyl or chromenyl, such as 4-methylthiazolyl or 7-hydroxy-2H-chromen-2-one-yl. The compound of formula (I) has the following formula:

One of them.

  Compounds of formula I include all isomers, physiologically acceptable salts (ie, pharmaceutically acceptable salts), hydrates, solvates, polymorphs, metabolites, and prodrugs. Things. Examples of isomers are stereoisomers (eg enantiomers and racemates) and tautomers.

  Also provided herein is a pharmaceutical composition comprising one or more compounds of formula (I), substructures and specific structures thereof, and a pharmaceutically acceptable excipient. A compound of formula (I) or a pharmaceutical composition comprising said compound is a disease, disorder which can be treated by inhibiting (ie blocking, reducing, preventing) the interaction between E-selectin and E-selectin ligand Or may be used in the methods described herein for treating or preventing symptoms. Such diseases and disorders include, for example, inflammatory responses and related inflammation, cancer, unwanted migration or migration of cells through the vasculature (eg, tumor cell metastasis), and thrombosis.

  A glycomimetic compound of formula (I) is used to treat any one or more of the diseases or conditions described herein, or to treat any one or more of the diseases or conditions described herein. It may be used to prepare or manufacture a medicament for use in treating. Each of these methods and uses are described in more detail herein.

Definitions As used herein, the following terms have the following meanings unless otherwise indicated. Certain chemical groups named herein are preceded by an abbreviation indicating the total number of carbon atoms found in the indicated chemical group.

As used herein, “C ₁ -C ₈ alkyl” or “C ₁ -C ₄ alkyl” refers to an alkane substituent having 1 to 8 carbon atoms or 1 to 4 carbon atoms, respectively. It can be linear, branched or cyclic (eg, cycloalkanyl). The term “alkanyl” may also be used herein and has the same meaning as alkyl. Examples include methyl (“Me”), ethyl, propyl, isopropyl, butyl and t-butyl. “C ₁ -C ₈ haloalkyl” refers to a C ₁ -C ₈ alkanyl substituted with at least one halogen (halo). When two or more halogens are present, the halogens present may be the same or different, or both (if at least three are present). “C ₂ -C ₈ alkenyl” or “C ₂ -C ₄ alkenyl” is an alkene substitution having 2 to 8 carbon atoms or 2 to 4 carbon atoms, respectively, with at least one carbon-carbon double bond. Refers to a group and may be linear, branched or cyclic (cycloalkenyl). The examples are similar to the “C ₁ -C ₈ alkyl” and “C ₁ -C ₈ alkyl” examples except that the alkenyl has at least one carbon-carbon double bond. “C ₂ -C ₈ haloalkenyl” refers to C ₂ -C ₈ alkenyl substituted with at least one halogen (halo). When two or more halogens are present, the halogens present may be the same or different, or both (if at least three are present). “C ₂ -C ₈ alkynyl” or “C ₂ -C ₄ alkynyl” are alkyne substituents having 2 to 8 carbon atoms or 2 to 4 carbon atoms, respectively, at least one carbon-carbon triple bond. And can be linear, branched or cyclic (cycloalkynyl). The examples are similar to the “C ₁ -C ₈ alkyl” and “C ₁ -C ₈ alkyl” examples, except that the alkanyl has at least one carbon-carbon triple bond. “C ₂ -C ₈ haloalkynyl” refers to “C ₂ -C ₈ alkynyl” substituted with at least one halogen (halo). When two or more halogens are present, the halogens present may be the same or different, or both (if at least three are present).

  A non-sugar mimetic moiety (M) is a moiety that imparts to the compound one or more advantageous properties that enhance the effectiveness and in vivo use of the compound. Examples of such properties include increased water solubility, decreased immunogenicity, improved stability, and improved pharmacokinetic profile. Improved pharmacokinetic profiles include those that improve increased serum half-life, decreased clearance, and therapeutic index.

  “Halo” (or “halogen” or “halide”) is a fluoro (F), chloro (Cl), bromo (Br), or iodo (I) radical.

  “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. The aryl radical may be monocyclic, bicyclic, tricyclic, or tetracyclic, and these may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, And aryl radicals derived from the hydrocarbon ring systems of preaden, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as “aralkyl”) is meant to include an optionally substituted aryl radical.

“Aralkyl” has the formula —R _b —R _c , wherein R _b is an alkylene chain as defined above, and R _c is one or more aryl radicals as defined above, eg, benzyl, diphenylmethyl , And trityl). Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

“Heterocyclyl”, “heterocycle”, or “heterocycle” is a stable containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Refers to a 3-24 membered non-aromatic ring radical. In certain embodiments, the heterocyclyl radical is a 5-10 membered heterocyclyl containing 3-9 carbon atoms and 1-3 heteroatoms. Unless stated otherwise specifically in the specification, a heterocyclyl radical may be monocyclic, bicyclic, tricyclic, or tetracyclic and may include fused or bridged ring systems, such as a nitrogen atom in a heterocyclyl radical. , Carbon atoms, or sulfur atoms may be optionally oxidized, nitrogen atoms may be quaternized, and heterocyclyl radicals may be partially saturated or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroin Drill, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, Trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 12-crown-4, 15-crown- , 18-crown -6,21- crown -7, aza-18-crown-6, diaza-18-crown-6, and aza-21-crown -7 and diaza-21-crown-7, it is. Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted.

“Heterocyclylalkyl” is a radical of the formula —R _b —R _c where R _b is an alkylene chain as defined above and R _c is one or more heterocyclyl radicals as defined above, eg, tetrahydrofuran Nyl-methyl, tetrahydropyranyl-methyl and the like). 6-membered heterocyclylalkyl refers to a heterocyclylalkyl where the heterocyclyl moiety has 6 atoms in the ring. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.

  “Heteroaryl” includes a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. Refers to a -14 membered ring system radical. In certain embodiments, the heteroaryl radical is a 5-10 membered heteroaryl containing 3-9 carbon atoms and 1-3 heteroatoms. For purposes of the present invention, heteroaryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic, and may include fused or bridged ring systems, such as the nitrogen atom in the heteroaryl radical, Carbon atoms or sulfur atoms may optionally be oxidized, and nitrogen atoms may optionally be quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1,4] dioxepinyl 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranyl, benzothienyl (benzothiophenyl), benzotria Zolyl, benzo [4,6] imidazo [1,2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanyl, isothiazolyl, imidazolyl, indazolyl, i Drill, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyrazinyl, 1-oxide Pyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinoclinyl, quinuclidinyl, isoquinolinyl, isoquinolinyl Norinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, Fine thiophenyl (i.e. thienyl) can be mentioned. Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted.

“Heteroarylalkyl” is a radical of the formula —R _b —R _c where R _b is an alkylene chain as defined above and R _c is one or more heteroaryl radicals as defined above, eg , Furanyl-methyl, pyridyl-methyl, etc.). 6-membered heteroarylalkyl refers to a heteroarylalkyl in which the heteroaryl moiety has 6 atoms in the ring. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.

  The compounds described herein can generally be used as the free acid or free base. Alternatively, the compounds can be used in the form of acid or base addition salts. Acid addition salts of free base amino compounds can be prepared according to methods well known in the art and can be formed from organic and inorganic acids. Suitable organic acids include (but are not limited to) maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid , Mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid and benzenesulfonic acid. Suitable inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid. Base addition salts of the free acid compounds of the compounds described herein can also be prepared by methods well known in the art and can be formed from organic and inorganic bases. Suitable inorganic bases include (but are not limited to) hydroxides or other salts such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum, and organic bases such as substituted An ammonium salt is mentioned. Thus, a “pharmaceutically acceptable salt” (or physiologically appropriate salt) of a compound of formula I and its substructures, as well as any and all substructures and specific compounds described herein. The term salt) is intended to encompass any and all pharmaceutically suitable salt forms.

  Compounds of formula I and its substructures and specific structures may be shown as anionic species. One skilled in the art will recognize that the compound is present with an equimolar ratio of cations. For example, the compounds described herein can exist in fully protonated form, or in the form of salts such as sodium, potassium, ammonium, etc., or in combination with any of the above inorganic bases. Where more than one anionic species is indicated, each anionic species can be present independently as a protonated species or a salt species. In some specific embodiments, the compounds described herein exist as sodium salts.

  Furthermore, some of the crystalline forms of any of the compounds described herein may exist as polymorphs, which are also included and contemplated in this disclosure. In addition, some of the compounds can form solvates with water or other solvents. Such solvates are similarly included within the scope of the compounds and compositions described herein.

With respect to stereoisomers, compounds of formula I and any substructures or specific structures described herein may have one or more chiral (or asymmetric) centers, so that absolute stereochemistry In terms of enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)-or (S)-. Where a compound described herein contains an olefinic double bond or other center of geometric asymmetry, unless otherwise specified, the compound is both E and Z geometric isomers (eg, cis or trans) It is intended to include. Similarly, unless otherwise specified, it is also intended to include all possible isomers, as well as their racemic and optically pure forms, and all tautomers. Accordingly, various stereoisomers and mixtures thereof are contemplated to include “enantiomers” (which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other). Thus, a compound can be any isomer, including racemates, racemic mixtures, and individual enantiomers or diastereomers. A tautomer refers to a proton transfer from one atom of a molecule to another atom of the same molecule.

  “Prodrug” is meant to indicate a compound that can be converted under physiological conditions or by solvolysis to the biologically active compounds described herein. Thus, the term “prodrug” refers to a metabolic precursor of a compound described herein that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound described herein. Prodrugs are typically rapidly transformed in vivo, for example, by hydrolysis in blood, to provide the parent compound described herein. Prodrug compounds often provide the advantage of solubility, histocompatibility or delayed release in mammals (eg, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, See Amsterdam). A discussion of prodrugs can be found in Higuchi, T. et al. C. S. Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

  The term “prodrug” is also meant to include any carrier bound by a covalent bond, which carrier is described herein when such prodrug is administered to a mammalian subject. The active compound is released in vivo. Prodrugs of the compounds described herein are described herein in such a way that the modification is cleaved, either routinely or in vivo, to become the parent compound described herein. Can be prepared by modifying functional groups present in the resulting compounds. A prodrug is a hydroxy, amino or mercapto group attached to any group that cleaves when the prodrug of the compound is administered to a mammalian subject to form a free hydroxy, free amino or free mercapto group, respectively. Including the compounds described herein. Examples of prodrugs include, but are not limited to, the hydroxy, carboxy, mercapto, or amino functional ester and amide derivatives of the compounds described herein.

Synthetic Procedures for Compounds Synthesis of compounds of Formula I (and substructures and specific compounds) was performed as described herein (including examples) using techniques well known to those skilled in the art. May be. A synthetic method for preparing the exemplary compounds described herein is described in Example 1. Said methods employ compounds of formula I by using appropriate reactants to prepare specific compounds using the techniques and methods described herein that are routinely practiced in the art. May be used to synthesize. As a further example, FIGS. 1 and 2 provide schematic diagrams of synthetic schemes for exemplary compounds described herein.

  In general, compounds of formula (I) can be prepared according to the following general reaction scheme I:

With respect to general reaction scheme I, structure A wherein R ¹ and R ² are as defined for formula (I) or are moieties that can be synthetically converted to R ¹ or R ² , Compounds of P ¹ are suitable protecting groups) can be purchased from commercial sources or prepared according to methods known in the art. Similarly, structure B (wherein R ⁸ is as defined for formula (I) or is a moiety that can be synthetically converted to R ⁸ and P ² is a suitable protecting group). These compounds can be purchased from commercial sources or prepared according to methods known in the art. Reaction of A with B under appropriate conditions (eg, bromine followed by tetraethylammonium bromide) followed by selective removal of P ¹ yields compounds of structure C.

In a parallel scheme, compound D (wherein P ³ is a suitable protecting group and P ⁴ is a suitable protecting group or synthetically manipulated to define R ³ (defined for formula (I)). Can be purchased or can be prepared according to known techniques. Reaction of D with a suitable activator (eg Cl ₃ CCN) gives the active compound E. Other suitable means for activating compounds of structure D are known to those skilled in the art. Coupling C and E under suitable conditions gives the compound of structure F.

By selectively removing P ³ followed by selective protection, compounds of structure G (where P ⁵ is a suitable protecting group) are obtained. G is H (wherein P ⁶ is a suitable protecting group, or is a moiety that can be synthesized to give R ⁴ (as defined for formula (I)), where R ⁵ is As defined for formula (I), LG is reacted with a suitably activated leaving group (eg, triflate, etc.) and deprotected to exemplify formula (I) Compound is obtained.

It will be appreciated that further synthetic manipulations may be desirable to obtain certain compounds of formula (I). For example, in certain embodiments, P ⁴ may be an allyloxy group that can be converted to give an alkylamide (eg, methyl). In other examples, R ¹ in the above scheme may be an alkenyl moiety, and the synthetic scheme involves reducing the alkene to an alkyl group. Various other modifications to the above general reaction scheme I (eg, changing the starting materials or modifying any of the reaction products to include other non-hydroxyl moieties at R ⁶ and / or R ⁷ ) Is possible. Methods for these and other modifications to the above exemplary scheme are well known in the art and are described in more detail by examples.

  Those skilled in the art will also note that the functionalities of the intermediate compounds may need to be protected with appropriate protecting groups in the methods described herein, even if not specifically described. You will recognize. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (eg, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include —C (O) —R ″ ″ (R ″ is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups can be added or removed according to standard techniques known to those skilled in the art and described herein. The use of protecting groups is described in Green, T .; W. and P.M. G. M.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley. As those skilled in the art are aware, the protecting group may also be a polymer resin such as Wang resin, Rink resin or 2-chlorotrityl chloride resin.

Reactants similar to those described above may be identified by an index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are found in most public and university libraries, and It is available through an online database (for more details you can contact the American Chemical Society, Washington, DC). Chemicals that are known but not commercially available in the catalog can be prepared by custom chemical synthesizers, and many of the standard chemical suppliers (eg, those listed above) provide custom synthesis services. Yes. For the preparation and selection of the pharmaceutical salts of the present disclosure, see p. H. Stahl & C. G. See Wermuth “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002.

In general, the compounds used in the reactions described herein start from general reaction scheme I, Examples 1 and 2, starting from commercially available chemicals and / or compounds described in the chemical literature, 1 and 2 and / or organic synthesis techniques known to those skilled in the art. “Commercial chemicals” include Acros Organics (Pittsburgh PA), Aldrich Chemical (including Milwaukee WI, Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chest PA), Cressent Chemical Co. (Happapage NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons
Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall UK), Lancaster Synthesis (Windham NH), Maybridge Chemical Co. Ltd .. (Cornwall UK), Paris Chemical Co. (Orem UT), Pfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rockford IL), Riedel de Haen AG (Hanoover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc. (Rockville MD), and Wako Chemicals USA, Inc. (Richmond VA) can be obtained from standard commercial sources.

Methods known to those skilled in the art can be ascertained from various reference books, papers, and databases. Suitable references and technical books detailing the synthesis of reactants useful for the preparation of the compounds of the present disclosure or providing references to articles describing the preparation include, for example, “Synthetic Organic” Chemistry, “John Wiley & Sons, Inc. , New York; R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed. , Academic Press, New York, 1983; O. House, “Modern Synthetic Reactions”, 2nd
Ed. , W .; A. Benjamin, Inc. Menlo Park, Calif. 1972; L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed. John Wiley & Sons, New York, 1992; March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure,” 4th Ed. , Wiley-Interscience, New York, 1992. Further suitable references and technical books detailing the synthesis of reactants useful for the preparation of the compounds of the present disclosure or providing references to articles describing the preparation include, for example, Fuhrhop, J. et al. and Penzlin G. et al. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Integrated Edition (1994) John Wiley & Sons ISBN: 3-527-29074-
5; Hoffman, R .; V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R .; C. “Complementary Organic Transformations: A Guide to Functional Group Preparations”, 2nd Edition, (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advantest. (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (Editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; “Patai's 19 2 Guide to the Chemistry of Functional Groups ”(1992) Interscience ISBN: 0-471-93022-9; Quin, LD et al.,“ A Guide to Organophosphorus Chemistry-4 ”. -31824-8; Solomons, TW G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., "Intermediate Organic Chemistry Chemistry 2" 1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ulmann's Encyclopedia” (1999) John Wiley & S5: Non-96. (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

As described above, in addition to the compounds described herein, binding to the compound at or near the binding site on E-selectin, and inhibition of the interaction between E-selectin and sLe ^a or sLe ^x Other agents that compete with the compound are provided. Examples of the other drugs include antibodies, polypeptides, peptides, and aptamers. Such agents can be produced by various means well known in the art. For example, E-selectin protein is used to generate an antibody library. The antibody library is screened for one or more antibodies of interest using a compound disclosed herein, such as compound 22 of FIG. 1A. Alternatively, for example, a portion of E-selectin that binds to compound 22 of FIG. 1A is identified and used to generate an antibody of interest (eg, using the portion as an immunogen). This portion of E-selectin may also be used to design and produce polypeptides, peptides, and aptamers that compete with the compounds described herein.

Antibodies and antigen-binding fragments thereof Agents that are E-selectin antagonists and may be useful in the methods and uses described herein, which may be antibodies, polypeptides, peptides, or aptamers, are also described herein. Provided in. Such agents bind to or near the binding site on E-selectin to which the compounds of formula (I) provided herein bind. Accordingly, these agents can bind to E-selectin in competition with the compound of formula I and can block (ie inhibit) the binding of E-selectin to the E-selectin ligand.

  Examples of the drug include an antibody that specifically binds to E-selectin or an antigen-binding site thereof. As described herein, the epitope to which such an antibody binds includes an amino acid at or near the binding site on E-selectin to which a compound provided herein binds. The epitope to which such an antibody binds may comprise one or more amino acids adjacent to the residue to which the compound provided herein binds and / or interacts with said compound, although not adjacent. It may contain one or more amino acid residues.

  As used herein, an antibody is "immunospecific", "specific" for an antigen of interest or antigen of interest when it reacts with the antigen at a detectable level. It is said to “specifically bind”. The affinity of the antibody and antigen-binding fragment thereof can be determined using conventional techniques such as those described by Scatchard et al. (Ann.NY. Acad. Sci. USA 51: 660 (1949)) and It can be readily determined by surface plasmon resonance (SPR) (see, eg, Wolff et al., Cancer Res. 55: 2560-2565 (1993)). The binding properties of an antibody to an antigen generally include, for example, immunity including enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, immunoblotting, countercurrent immunoelectrophoresis, radioimmunoassay, dot blot analysis, inhibition assay or competitive assay. Detection methods can be used to determine and evaluate and can be readily performed by one of ordinary skill in the art (eg, US Pat. No. 4,376,110 and US Pat. No. 4,486). , 530; Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988)).

  These specific antibodies may be polyclonal or monoclonal and are prepared by immunizing animals followed by isolating antibodies or routinely practiced in the art. Cloned from specific B cells according to the methods and techniques described in the specification. A variable region or one or more complementarity determining regions (CDRs) may be identified and isolated from an antigen-binding fragment or peptide library. The antibody or antigen-binding fragment thereof may be designed by recombinant techniques and / or produced by recombinant techniques.

  The antibody may belong to any immunoglobulin class. It can be animals, such as poultry (eg chickens) and mammals (including but not limited to mice, rats, hamsters, rabbits, or other rodents, cattle, horses, sheep, goats, camels, humans, or other May be obtained from or derived from primates). The antibody may be an internalizing antibody. Antibodies can generally be prepared by any of a variety of techniques known to those skilled in the art and described herein. See, for example, Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1988); Peterson, ILAR J. et al. 46: 314-19 (2005); Kohler and Milstein (Nature, 256: 495-97 (1976); Eur. J. Immunol. 6: 511-19 (1975); Coligan et al. (Eds.), Current Protocols in See Immunology, 1: 2.5.1-2.6.7 (John Wiley & Sons 1991).

Human monoclonal anti-E-selectin antibodies can be made by several techniques well known to those of skill in the art (eg, US Pat. No. 4,464,456; Lonberg et al., Nature 368: 856 (1994); U.S. Patent No. 5,877,397; Bruggemann et al., Curr.Opin.Biotechnol.8: 455-58 (1997); Jakobovits et al., Ann.N.Y.Acad.
. Sci. 764: 525-35 (1995)); (WO 92/02551 pamphlet; US Pat. No. 5,627,052; Babcook et al., Proc. Natl. Acad. Sci. USA 93: 7843-48 ( 1996); or other techniques known in the art). Chimeric antibodies (including humanized chimeric antibodies) specific for a portion of the E-selectin of interest can also be generated. For example, Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-55 (1984); Shin et al., Methods Enzymol. 178: 459-76 (1989)). Strategies for designing humanized antibodies are routinely practiced in the art (eg, Jones et al., Nature 321: 522-25 (1986); Riechmann et al., Nature 332: 323-27 (1988)); Padlan et al., FASEB 9: 133-39 (1995); Chothia et al., Nature, 342: 377-83 (1989); Bajorath et al., Ther. Immunol. 2: 95-103 (1995)).

For certain applications, antigen-binding fragments of antibodies may be desirable. Antibody fragments, F (ab ′) ₂ , Fab, Fab ′, Fv, and Fd can be obtained, for example, by proteolytic hydrolysis of the antibody (eg, Weir, Handbook of Experimental Immunology, Blackwell Scientific, Boston ( 1986)), or may be prepared synthetically or genetically engineered. Antibody fragments include a recombinant single-chain polypeptide molecule in which a light chain variable region and a heavy chain variable region are connected by a peptide linker (scFv protein), and a minimal recognition unit consisting of amino acid residues that mimic the hypervariable region (Including at least one CDR). Methods and techniques for preparing and isolating antibody fragments have been described in the art (see, eg, Larrick et al., Methods: Methods of Methods in Enzymology 2: 106, (1991); Courtenay-Luck, in Monoclonal Antibodies: Production, Engineering and Clinical Application, Ritter et al., (Eds.), Page 166 (Cambridge University Press in 1995); and Ward et al., In c. Wi ey-Liss, Inc. 1995); International Application No. PCT / US91 / 08694 and International Application No. PCT / US91 / 04666); Scott et al., Science 249: 386 (1990); Devlin et al., Science 249. : 404 (1990); Cwirla et al., Science 276: 1696-99 (1997); US Patent No. 5,223,409; US Patent No. 5,733,731; US Patent No. 5,498, No. 530; US Pat. No. 5,432,018; US Pat. No. 5,338,665; US Pat. No. 5,922,545; WO 96/40987 and (See WO 98/15833 pamphlet).

Antibodies may also be identified and isolated from human, rabbit, mouse, or chicken immunoglobulin phage libraries. Antibodies isolated from non-human species or non-human immunoglobulin libraries may be genetically engineered to “humanize” the antibody or fragment thereof. For example, Winter et al., Annu. Rev. Immunol. 12: 433-55 (1994); Burton et al., Adv. Immunol. 57: 191-280 (1994); U.S. Patent No. 5,223,409; Huse et al., Science 246: 1275-81 (1989); Kang et al., Proc. Natl. Acad. Sci. USA
88: 4363-66 (1991); Hoogenboom et al., J. MoI. Molec. Biol. 227: 381-388 (1992); U.S. Pat. No. 6,703,015)
checking ...

Agents that are E-selectin antagonists also include peptide-immunoglobulin (Ig) constant region fusion polypeptides, including peptide-IgFc fusion polypeptides. The peptide may be any naturally occurring molecule or a molecule prepared by recombinant techniques. Peptide-Ig constant region fusion polypeptides such as peptide-IgFc fusion polypeptides (also referred to in the art as peptibodies (see, eg, US Pat. No. 6,660,843)) A biologically active peptide or polypeptide capable of altering the sLe ^a or sLe ^x binding function of E-selectin, ie a portion, ie at least one constant region domain (eg CH1, CH2, CH3 And / or peptides or polypeptides fused in-frame with CH4). Antibody-related sequences are described in Kabat et al. (In Sequences of
Proteins of Immunological Interest, 4th ed. (US Dept. of Health and Human Services, US Government Printing Office, 1991).

Peptides and Peptidomimetics In certain embodiments, some peptides or peptidomimetics of E-selectin that bind to a compound provided herein provide ^a potential between E-selectin and sLe ^a or sLe ^x . The interaction may be inhibited (ie, inhibited, reduced, destroyed, reduced in a biologically or statistically significant manner). The peptide portion of the peptide and peptidomimetic is at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16-20, 21-25, 26-30, 31 It may contain ~ 35, 36-40, 41-45, or 46-50 amino acids. Peptides and peptidomimetics typically have a molecular weight of less than 10 ⁴ daltons, less than 10 ³ daltons, or less than 10 ² daltons.

Methods of Use Prevention of diseases or disorders associated with, mediated by, or exacerbated by binding of E-selectin to an E-selectin ligand, which then causes undesired biological activity (ie, To reduce and reduce the likelihood of its onset or recurrence) and / or treatment, the E-selectin antagonists described above and herein (glycomimetics of the formula (I), antibodies or antigen-binding fragments thereof, poly Provided herein are methods for using any one or more of peptides, peptides, and aptamers). Accordingly, the E-selectin antagonists described herein may be used in a method for treating a disease or disorder treatable by inhibiting the binding of E-selectin to an E-selectin ligand. These methods and other embodiments are described in more detail herein.

In certain embodiments, a compound of formula (I) or a pharmaceutical composition comprising said compound is administered to an individual in need of treatment and prevention of cancer cell metastasis by administering said compound or composition to the individual. That is, it can also be used in a method for treating and preventing (ie, reducing or reducing the likelihood of developing) metastasis of cancer cells (also referred to herein as tumor cells) in a subject, patient). Good. In other embodiments, a compound of formula (I) or a pharmaceutical composition comprising said compound is administered to an individual in need of inhibition of invasion of cancer cells into the bone marrow by administering said compound or composition to the individual ( That is, it may be used in a method for inhibiting (reducing, reducing, or preventing (ie, reducing the possibility of developing)) cancer cells from infiltrating the bone marrow in a subject or patient. In yet another embodiment, for inhibiting (reducing, reducing or preventing) cancer cells expressing an E-selectin ligand from adhering to endothelial cells expressing E-selectin on the cell surface of endothelial cells. A method wherein the compound interacts with E-selectin on the endothelial cell such that binding of the cancer cell to the endothelial cell is inhibited (ie, the compound or a composition comprising the compound is Provided herein is a method comprising contacting the endothelial cell with the compound or a composition comprising the compound (in some manner that allows it to interact with the endothelial cell). In certain embodiments, the endothelial cells are present in the bone marrow. In another embodiment, an E-selectin antagonist agent selected from antibodies or antigen-binding fragments thereof, polypeptides, peptides, and aptamers, which can compete with a compound of formula (I) May be used in the above method.

  In yet another embodiment described herein, for treating cancer in an individual (ie, subject, patient) by administering to the individual a compound of formula I or a pharmaceutical composition comprising said compound. A method is provided. The compound (or pharmaceutical composition comprising the compound) may be administered in conjunction with chemotherapy or radiation or both (ie, as an adjunct therapy, also referred to as additional treatment). Chemotherapy or radiation therapy or a combination thereof may be referred to as a primary anti-tumor or anti-cancer therapy to be performed on an individual to treat a particular cancer. In another embodiment, an E-selectin antagonist agent selected from antibodies or antigen-binding fragments thereof, polypeptides, peptides, and aptamers, which can compete with a compound of formula (I) May be used in the above method.

  In yet another embodiment, a compound of formula I or a pharmaceutical composition comprising said compound may be used in a method for enhancing the survival of hematopoietic stem cells in a subject. In another embodiment, an E-selectin antagonist agent selected from antibodies or antigen-binding fragments thereof, polypeptides, peptides, and aptamers, which can compete with a compound of formula (I) May be used in the above method.

  In another embodiment, a compound of formula I or a pharmaceutical composition comprising said compound is used in a method for treating or preventing thrombosis in a subject (ie, reducing or reducing its likelihood or risk). May be. In certain embodiments, a compound of Formula I or a pharmaceutical composition comprising said compound is for treating or preventing thrombus formation in an individual in need of such treatment (ie, reducing or reducing the risk of onset). Comprising administering to said individual a compound having the formula (I), or any substructure or specific structure described herein (or a pharmaceutical composition comprising said compound) May be used in the method. In another embodiment, an E-selectin antagonist agent selected from antibodies or antigen-binding fragments thereof, polypeptides, peptides, and aptamers, which can compete with a compound of formula (I) May be used in the above method.

As understood by those of ordinary skill in the medical arts, the terms “treat” and “treatment” refer to medical management of a disease, disorder, or condition in a subject (ie, patient, individual) (eg, Stedman See 's Medical Dictionary.) In general, a suitable dose and treatment regimen will provide at least one glycomimetic compound or other agent described herein in an amount sufficient to provide a therapeutic and / or prophylactic effect. A therapeutic and / or prophylactic effect includes, for example, improvement of both clinical outcomes, therapeutic treatments and prophylactic or preventative measures, the purpose of which is undesirable physiological changes Or preventing or delaying or suppressing (decreasing) a disorder, or preventing or delaying or suppressing (decreasing) the spread or severity of such a disorder. As discussed herein, beneficial or desired clinical results from treatment of a subject include, but are not limited to, symptoms resulting from or associated with the disease, condition, or disorder to be treated Reduced, reduced, or alleviated; reduced onset of symptoms; improved quality of life; long-term disease-free state (ie, reduced likelihood or tendency of subject to present symptoms based on disease diagnosis being made) Reduced disease extent; stabilized disease state (ie, does not worsen); delayed or delayed disease progression; improved or reduced disease state; and remission (whether detectable or undetectable) Partial or complete); and / or overall survival. “Treatment” can also mean prolonging survival as compared to expected survival if the subject does not receive treatment. Subjects in need of treatment include those who already have a disease, symptom, or disorder, as well as subjects who have or are at risk for developing the disease, symptom, or disorder, and the disease, symptom Or a person who should prevent (ie, reduce the likelihood of developing a disease, condition, or disorder) a disorder.

  As discussed in more detail herein, the disease or disorder to be treated or prevented (ie, reduced the likelihood of its onset or recurrence) is cancer and related metastases, cancers including solid tumors, and Examples include cancers including humoral tumors. As shown in FIG. 3, E-selectin plays a central role in cancer progression. The invasive properties of cancer cells depend at least in part on the ability of the cancer cells to disrupt the endothelial barrier. Cancer cells, eg, colon cancer cells, may express an E-selectin ligand that can bind to endothelial cells that express E-selectin on the cell surface. Without being bound by theory, the binding of cancer cells to endothelial cells can contribute to cancer cell migration (see, eg, Tremblay et al., Oncogene 25: 6563-6573. Doi: 10.1038 / sj. onc.l209664; published online 22 May 2006).

  Cancers that can be prevented from metastasizing include cancers including solid tumors and those including humoral tumors (eg, hematological malignancies). Examples of solid tumors that can be treated with agents described herein (eg, glycomimetic compounds of Formula I) include colorectal cancer, liver cancer, stomach cancer, lung cancer, brain cancer, kidney cancer, bladder cancer Thyroid cancer, prostate cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, melanoma, breast cancer, and pancreatic cancer. Humoral tumors occur in the blood, bone marrow, and lymph nodes, and include leukemia (eg, AML, ALL, CLL, and CML), lymphomas (eg, non-Hodgkin and Hodgkin lymphomas), and myeloma (eg, multiple multiples). Myeloma). Reports describe that humoral tumors such as multiple myeloma follow the metastatic cascade observed in similar infiltrating-solid tumors, and that E-selectin ligand is present on humoral tumor cells such as myeloma cells. (See, for example, Ghobrial, Blood 120: 20-30 (2012) Epub 2012 Apr 24). In others, it has been observed that E-selectin ligands (eg, CD65) can be important for extravascular invasion of leukemia cells (eg, Noguchi et al., Leukemia Res. 25: 847-53 (2001)). checking). Humoral tumor cells also adhere to the bone marrow, which can further lead to tumor cell sequestration and cessation, making the tumor cells “resistant” to chemotherapy (this phenomenon is referred to as adhesion-mediated drug resistance). ) Studies have also shown that bone marrow contains an anatomical region containing a special endothelium that expresses E-selectin (see, eg, Shipkins et al., Nature 435: 969-973 (2005)). . Thus, E-selectin antagonists such as those described herein inhibit the metastasis of cancer, including either solid or humoral tumors, by inhibiting the binding of E-selectin ligand to E-selectin. Can be useful to do.

In certain embodiments, the compounds of formula (I), including substructures and specific compounds, and agents described herein, are individuals (ie, test subjects) in need of treatment or prevention of cancer cell metastasis. It may be used to treat or prevent (ie, reduce or reduce the likelihood of developing) cancer cell metastasis in the body (patient). The compounds and agents described herein inhibit or prevent cancer cells from infiltrating the bone marrow in individuals in need of inhibition or prevention of cancer cell infiltration into the bone marrow (ie, reduce the likelihood of its onset). Or may be used to reduce). An individual (or subject) in need of such treatment includes an individual who has been diagnosed with either cancer, ie, cancer comprising a solid tumor, or cancer comprising a humoral tumor. Without being bound by theory, inhibiting tumor cells from transferring to the bone marrow or other protective niches in the body isolates or protects the tumor cells from exposure to chemotherapy or radiation therapy. Is obstructed.

  Examples of such cancer include colorectal cancer, liver cancer, stomach cancer, lung cancer, brain cancer, kidney cancer, bladder cancer, thyroid cancer, prostate cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer. Melanoma, breast cancer, and pancreatic cancer. Humoral tumors arise in the blood, bone marrow, sponge-like soft tissue, mostly in the center of the bone, and lymph nodes, and include leukemia (eg, AML, ALL, CLL, and CML), lymphoma, and myeloma (eg, , Multiple myeloma). Lymphomas include Hodgkin lymphoma characterized by the presence of a type of cell called Reed Stamberg cells, and non-Hodgkin lymphoma including a diverse group of cancers of the immune system cells. Non-Hodgkin lymphoma can be further divided into cancers that have a painless (slow growth) period and cancers that have an aggressive (fast growth) period, and these subtypes differ in their response to treatment.

  A compound of formula I and an agent described herein (or a pharmaceutical composition comprising said compound or agent) are delivered to a subject as a primary therapy for treating cancer or chemotherapy or radiation therapy thereof It may be administered as both adjuvant therapies. The chemotherapy and radiation therapy that can be performed depends on several factors, including the type of cancer, the location of the tumor, the stage of the cancer, the age and sex of the subject, and general health. One of ordinary skill in the medical arts can readily determine an appropriate chemotherapy or radiation therapy plan for a subject in need. A person skilled in the medical arts will also know when to administer a compound or agent of formula (I) to a subject (ie, whether the compound or agent is administered prior to the cycle of primary chemotherapy or radiation treatment). Whether to be administered at the same time or after this) can be determined by preclinical and clinical studies.

  A method for inhibiting adhesion of tumor cells expressing an E-selectin ligand to endothelial cells expressing E-selectin on the cell surface, the endothelial cells being described herein. Contacting with a compound or agent of formula (I), thereby allowing the compound to interact with E-selectin on the surface of the endothelial cells and inhibiting the binding of the tumor cells to the endothelial cells Also provided herein is a method comprising: Without being bound by theory, inhibition of tumor cell adhesion to endothelial cells significantly reduces the ability of tumor cells to migrate to other organs, blood vessels, lymph, or bone marrow, thereby causing cancer progression. Can be reduced, reduced, or inhibited or delayed (including mitigating, reducing, inhibiting or delaying metastasis).

  In certain embodiments of the methods described herein, the subject is a human or non-human animal. A subject in need of the treatment described herein may exhibit symptoms or sequelae of the cancer disease, disorder, or symptom described herein, or said disease, disorder, or symptom. You may have a risk of developing. Non-human animals that can be treated include, for example, non-human primates (eg, monkeys, chimpanzees, gorillas, etc.), rodents (eg, rats, mice, gerbils, hamsters, ferrets, rabbits), rabbits, pigs (Eg, pigs, minipigs), horses, dogs, cats, cows, and other domestic animals, livestock, and zoo animals.

  One of ordinary skill in the medical and clinical arts will be able to treat or prevent the diseases or disorders or conditions described herein and determine and adjust appropriate dosage regimens (eg, the amount of compound per dose and The efficacy of the compounds, agents, or pharmaceutical compositions described herein can be readily determined in (/ or adjusting the frequency and frequency of administration). Diagnostic methods including physical examination, evaluation and monitoring of clinical symptoms, and the results of one or any combination of the analytical tests and methods described herein are used to monitor a subject's health Also good.

  As described herein, for the treatment of a subject (ie, an individual) who has cancer or is at risk of developing cancer, at least one of the above agents (eg, a compound of formula (I)). (Ie, one or more) may be administered in combination with at least one (ie, one or more) additional anticancer agents. Chemotherapy may include one or more chemotherapeutic agents. For example, chemotherapeutic agents, radiation therapy agents, phosphoinositide-3 kinase (PI3K) inhibitors, VEGF inhibitors may be used in combination with the agents described herein. An example of a PI3K inhibitor includes the compound named “XL499” by Exelixis. An example of a VEGF inhibitor includes a compound called “cabo” (formerly known as XL184). Many other chemotherapeutic drugs are small organic molecules. As understood by those skilled in the art, chemotherapy can also refer to a combination of two or more chemotherapeutic drug molecules administered in a coordinated manner and can be referred to as combination chemotherapy. A number of chemotherapeutic drugs are used in the oncology field, including, for example, alkylating agents; antimetabolites; anthracyclines, plant alkaloids; and topoisomerase inhibitors.

  An E-selectin antagonist such as a glycomimetic compound of formula (I) may function independently of the anticancer agent, or in concert with the anticancer agent (eg, by enhancing the effectiveness of the anticancer agent, or And vice versa). In one embodiment, a method for treating cancer is provided that comprises administering an E-selectin antagonist (including a glycomimetic compound of Formula I) as described herein. The cancer may be a solid tumor or a liquid tumor. In certain embodiments, E-selectin antagonists are used in combination with chemotherapy, radiation, or both chemotherapy and radiation. When multiple cycles of chemotherapy or radiation therapy are administered to a subject to treat cancer, the E-selectin antagonist is administered for one or more cycles (ie, 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles). Or more cycles) of chemotherapy or radiation therapy. E-selectin antagonists may enhance the effectiveness of chemotherapeutic agents or radiation therapy.

In another embodiment, hematopoietic stem cell (HSC) survival is enhanced (ie, enhanced, promoted, improved) in a subject that is or will be treated with a chemotherapeutic drug or radiotherapy, respectively. A method of maintaining or maintaining in a statistically or biologically significant manner, comprising administering one or more of the E-selectin antagonist glycomimetic compounds described herein. Provided herein. In certain embodiments, the subject is undergoing or will receive both chemotherapy and radiation therapy. It also reduces (ie, reduces, inhibits, decreases) the sensitivity or chemosensitivity of hematopoietic stem cells (HSC) to chemotherapeutic drugs or radiation therapy, respectively, in a subject in a statistically or biologically significant manner. A method for providing is provided herein. Since repeated cycles of chemotherapy and radiation therapy often reduce the ability of HSCs to restore and replenish the bone marrow, the glycomimetic compounds described herein can have two or more cycles, eg, at least two cycles, It may be useful for subjects who are scheduled to receive three or four or more cycles of chemotherapy or radiation therapy or a combination of both chemotherapy and radiation therapy. Thus, each E-selectin antagonist may be administered to a subject with any one or more cycles of chemotherapy or radiation therapy (or combination). HSCs are present in the bone marrow and produce the cells necessary to replenish the immune system and blood. Anatomically, the bone marrow contains a vascular niche adjacent to the myeloid sinusoid endothelium (eg, Kiel et al., Cell 121: 1109-21 (2005); Sugiyama et al., Immunity 25: 977-88 (2006)); -See Ferrer et al., Nature 466: 829-34 (2010); Butler et al., Cell Stem Cell 6: 251-64 (2010)). Recent studies have demonstrated that E-selectin promotes HSC proliferation and is an important component of the vascular niche (eg, Winkler et al., Nature Medicine published online 21 October 2012; doi: 10.1038 / nm.2969; see also, for example, WO 2007/028050). Deletion or inhibition of E-selectin enhanced HSC survival and accelerated blood neutrophil recovery in mice treated with chemotherapeutic agents or radiation therapy (see, eg, Winkler et al., Supra). ).

  Agents described herein (ie, E-selectin antagonists such as glycomimetic compounds of formula (I)) may function independently of anticancer agents or in concert with anticancer agents (eg, May function by enhancing the effectiveness of an anti-cancer agent, or vice versa). In addition, one or more of the E-selectin antagonists described herein may be administered in conjunction with one or more other treatments, eg, to reduce the toxicity of the treatment. For example, at least one (ie, one or more) palliatives may be administered to (at least partially) neutralize the side effects of the treatment (eg, anti-cancer treatment). Agents (chemical or biological) that promote, ameliorate, or neutralize the side effects of antibiotic or corticosteroid administration are examples of such palliatives. At least one agent described herein is administered before, after, or concurrently with the administration of at least one additional anticancer agent, or at least one palliative to reduce the side effects of treatment. May be. Where administration is simultaneous, the combination may be administered from a single container or from two (or more) separate containers.

  Cancer cells that can be prevented (ie, inhibited, delayed) from metastasizing, killed, prevented from adhering to endothelial cells, or inhibited from infiltrating the bone marrow (as used herein) , Also referred to as tumor cells) include cells of solid tumors and humoral tumors (including hematological malignancies). Examples of solid tumors are described herein and include colorectal cancer, liver cancer, stomach cancer, lung cancer, brain cancer, kidney cancer, bladder cancer, thyroid cancer, prostate cancer, ovarian cancer, cervical cancer, uterine cancer Endometrial cancer, melanoma, breast cancer, and pancreatic cancer. Humoral tumors arise in the blood, bone marrow, and lymph nodes, and include leukemias (eg, AML, ALL, CLL, and CML), lymphomas (eg, Hodgkin lymphoma and non-Hodgkin lymphoma), and myeloma (eg, multiple tumors). Myeloma). As used herein, the term cancer cell includes mature, precursor and cancer stem cells.

Bone is a common place where cancer invades away from the primary tumor site. Cancer, when present in bones, often causes pain for an individual. In addition, if the particular bone affected is the source of blood cells in the bone marrow, the individual can develop various blood cell related disorders. Breast cancer and prostate cancer are examples of solid tumors that migrate to the bone. Acute myeloid leukemia (AML) and multiple myeloma (MM) are examples of liquid tumors that migrate to the bone. Cancer cells that migrate to the bone will typically migrate to the endosteal region of the bone marrow. When cancer cells infiltrate the bone marrow, they become quiescent and protected from chemotherapy. The compounds of the present invention block disseminated cancer cells from infiltrating the bone marrow. Various individuals can benefit from treatment with the compound. Examples of such individuals include individuals with a cancer type that has a tendency to migrate to bone, in which case the tumor is still localized or the tumor is disseminated but the bone is still infiltrated Individuals who are not or have such a cancer type are in remission.

Identify the cancer patient population most likely to respond to treatment using the agents described herein (eg, compounds of formula (I)) based on the mechanism of action of E-selectin. Can do. That is, when determined by the genetic polymorphism of S128R E-selectin, patients expressing highly active E-selectin may be selected (Alessandro et al., Int. J. Cancer 121: 528-535, 2007). In addition, E-selectin binding ligand (sialyl), as determined by antibodies directed against the cancer associated antigen CA-19-9 (Zheng et al., World J. Gastroenterol. 7: 431-434, 2001) and CD65. Patients may be selected for treatment with the agents described herein based on increased expression of Le ^a and sialyl Le ^x ). In addition, antibodies HECA-452 and FH-6 that recognize similar carbohydrate E-selectin ligands are used in diagnostic assays to select the cancer patient population most likely to respond to this treatment. Also good.

In other embodiments, methods are provided for treating or preventing (ie, reducing the likelihood of developing) thrombosis in a subject (ie, individual, patient) in need of treatment or prevention of thrombosis. . The subject may have a thrombus or may be at risk of developing a thrombus. The E-selectin antagonists (including compounds of formula (I)) described herein can inhibit or prevent (ie, reduce the likelihood of developing) thrombus formation. An E-selectin antagonist can inhibit, retard or inhibit thrombus formation or reduce the size or integrity of the thrombus formed. This method is generally applicable to individuals in need thereof, but is particularly beneficial for such individuals who also have a risk of bleeding. For example, this method is useful and beneficial in a wide variety of situations where the risk of bleeding is high and the use of antithrombotic agents with anticoagulant properties (eg, LMW heparin) is contraindicated. This method provides a benefit if bleeding still occurs, even though the use of antithrombotic agents with anticoagulant properties is not considered contraindicated. The E-selectin antagonist used in the method inhibits the interaction of E-selectin with sialyl Le ^a (sLe ^a ) or sialyl Le ^x (sLe ^x ), but in contrast to drugs such as heparin, It is a drug that does not significantly delay clotting.

  Selectin-mediated activation of leukocytes promotes the formation of procoagulant microparticles rich in tissue factor (see, eg, Wakefield et al., Thrombosis Res. 123: S3.5-40 (2009)). Both E and P-selectin are expressed on the endothelium after vessel wall injury or activation. Many reports have focused in part on the role of P-selectin in thrombosis due to the availability of P-selectin inhibitors (see, for example, Lopez et al., Hematology Am. Soc. Hematol. Educ. Program 439-). 56 (2004)); however, some studies have concluded that E-selectin has a major role. Without being bound to any particular theory, VTE formation is induced by an inflammatory response and selectins function in the early events of thrombosis.

  Various drugs are currently used to treat thrombosis. Exemplary drugs include those that inhibit platelet aggregation (antiplatelet drugs), such as aspirin, ticlopidine, eicosapentaenoic acid (EPA), dipyridamole, and dilazep hydrochloride. Antiplatelet drugs such as aspirin inhibit thrombus formation at the site of vascular injury by inhibiting the occurrence of blood coagulation triggered by platelet aggregation. However, since platelets also prevent bleeding from blood vessels, excessive inhibition of platelets can lead to a decrease in the effectiveness of platelets in preventing bleeding.

  Anticoagulants used for the treatment or prevention of thrombosis act by inhibiting blood clotting factors and include warfarin, heparin, low molecular weight heparin, and argatroban. Anticoagulants are useful for preventing intravascular fibrin thrombus formation, whereas fibrinolytic agents (eg, plasminogen activator) are useful for the degradation of fibrin thrombus. Uncontrolled bleeding can occur after prolonged administration of large doses of anticoagulant or fibrinolytic agent. When using heparin, complications include heparin resistance, bleeding, heparin-induced thrombocytopenia, and osteoporosis.

In particular, E-selectin plays a major role in thrombus formation, which was determined in animal models and by studying humans with the E-selectin genetic polymorphism (Ser128Arg). In human studies, a single nucleotide polymorphism (SNP) S128R in the E-selectin gene (serine to arginine at position 128) is associated with atherosclerosis, restenosis, coronary heart disease, myocardial infarction, and poor prognosis. Excess has been reported in patients with colorectal cancer (Myers et al., J. Surg. Res. 108: 212-21 (2002)). S128R E-selectin is a more active genetic variant than normal (ie wild type) E-selectin. Cells expressing S128R E-selectin show higher adherence and adhere to a greater variety of cell types (Yoshida et al., Arterioscler. Thromb. Vase. Biol. 23: 783-88 (2003)). According to publications and screening by Consortium of Functional Glycomics, S128R E-selectin binds to the same carbohydrate (sialyl Le ^a and / or sialyl Le ^x ) as wild-type E-selectin, but its binding in other in vitro assays The activity is enhanced and probably more non-specific.

  In a study of the effect of S128R E-selectin on venous thromboembolism (VTE), 585 patients were previously observed after the first VTE recurrence after treatment interruption (see, eg, Jilma et al., Arch. Inter. Med. 166: 1655-59 (2006)). In patients with S128R E-selectin, the development of another thrombus after discontinuation of anticoagulant therapy was significantly increased compared to patients with wild-type E-selectin.

  In one embodiment, the thrombosis is venous thromboembolism (VTE). VTE causes deep vein thrombosis and pulmonary embolism. Low molecular weight (LMW) heparin is the current mainstay therapy for preventing and treating VTE. However, there are many situations where the use of LMW heparin is contraindicated. Patients undergoing surgery, patients with thrombocytopenia, patients with a history of stroke, and many cancer patients are just a few examples where heparin should be avoided due to the risk of bleeding.

  As is apparent herein, administration of the compound of formula I significantly inhibited VTE in an in vivo treatment model of thrombus formation without increasing the risk of bleeding under continuous blood flow. The effect of the compound in this treatment model is comparable to standard therapy using LMW heparin. However, LMW heparin is a known anticoagulant and delays coagulation more than 4 times longer than the control bleeding time. As also described herein, the compounds of Formula I are only slightly delayed in clotting and significantly improve bleeding time over LMW heparin. Thus, the agents described herein may be useful when the risk of bleeding is not significant, but the risk of bleeding is significant, and in particular, antithrombotic agents that have anticoagulant properties (eg, LMW It can also be useful in a wide variety of situations where the use of heparin is contraindicated.

At least one (ie, one or more) of the agents (ie, an E-selectin antagonist such as a glycomimetic compound of formula (I)) and at least one (ie, one or more) additional antithrombotic agents Combinations may be administered. Agents described herein (ie, E-selectin antagonists) may function independently of antithrombotic agents or may function in concert with antithrombotic agents. In addition, one or more of the agents described herein may be administered in conjunction with one or more other treatments, for example, to reduce the toxicity of the treatment. For example, at least one palliative may be administered to (at least partially) neutralize the side effects of treatment. Agents (chemical or biological) that promote, ameliorate, or neutralize the side effects of antibiotic or corticosteroid administration are examples of such palliatives. The at least one agent described herein may comprise at least one additional antithrombotic agent, or at least one palliative to reduce the side effects of the treatment, after these administration, or these administrations. It may be administered at the same time. Where administration is simultaneous, the combination may be administered from a single container or from two (or more) separate containers.

  A wide variety of individuals are candidates for the treatments described herein. Thrombus formation can occur in infants, children, teenagers and adults. The individual may have a genetic predisposition for thrombosis. Thrombosis can be initiated, for example, by a medical condition (eg, cancer or pregnancy), a medical procedure (eg, surgery) or an environmental condition (eg, long-term bedside). Other individuals at risk for thrombus formation include those that have previously shown thrombus.

  In certain embodiments of the methods described herein, the subject is a human or non-human animal. A subject in need of the treatment described herein may exhibit symptoms or sequelae of the thrombotic disease, disorder, or symptom described herein, or the disease, disorder, or You may be at risk of developing symptoms. Non-human animals that can be treated include, for example, non-human primates (eg, monkeys, chimpanzees, gorillas, etc.), rodents (eg, rats, mice, gerbils, hamsters, ferrets, rabbits), rabbits, pigs (Eg, pigs, minipigs), horses, dogs, cats, cows, and other domestic animals, livestock, and zoo animals.

  One of ordinary skill in the medical and clinical arts will be able to treat or prevent the diseases or disorders or conditions described herein and determine and adjust appropriate dosage regimens (eg, the amount of compound per dose and The efficacy of the compounds, agents, or pharmaceutical compositions described herein can be readily determined in (/ or adjusting the frequency and frequency of administration). Diagnostic methods including physical examination, evaluation and monitoring of clinical symptoms, and the results of one or any combination of the analytical tests and methods described herein are used to monitor a subject's health Also good.

Methods for Characterization of Therapeutic Agents Characterization of at least one biological activity of the therapeutic agents described herein has been routinely practiced in the art and is described herein or in the art. May be determined by performing one or more in vitro and in vivo studies described in. In vitro assays include, but are not limited to, binding assays, immunoassays, competitive binding assays, and cell-based activity assays. Animal model studies may also be performed for in vivo drug characterization (including efficacy determinations), which are typically described in the art or those skilled in the art. Rodent research that has been routinely developed or adapted by. Non-human primate animal models may be used in preclinical studies prior to clinical studies; however, these animal models are typically designed to assess the efficacy or other characteristics of therapeutic agents It should not be used in the same routine way as in rodent studies. One skilled in the art of animal model study design and execution can also readily determine the appropriate control group to include in the study and determine one or more appropriate statistical analyzes to evaluate the data. You can also

Inhibition assays may be used to screen for E-selectin antagonists. For example, a compound or other agent described herein inhibits the interaction of E-selectin with sLe ^a or sLe ^x (ie, reduced, blocked, reduced, in a statistically or biologically significant manner). An assay may be performed to characterize the ability to (or prevent). The inhibition assay may be a competitive binding assay that allows the determination of IC ₅₀ values. By way of example, the method includes immobilizing an E-selectin / Ig chimera on a matrix (eg, typically a multiwell plate made of a polymer such as polystyrene; a test tube, etc.); adding a composition Reducing non-specific binding (eg, a composition comprising skim milk or bovine serum albumin or other blocking buffer routinely used by one skilled in the art); in the presence of sLe ^a comprising ^a reporter group, sLe ^a Contacting the immobilized E-selectin with the candidate agent under conditions and for a time sufficient to allow the immobilized E-selectin to bind; washing the immobilized E-selectin; and immobilization and detecting the amount of sLe ^a bound to reduction E- selectin. Those skilled in the art can easily and routinely achieve such process verification.

  Those skilled in the art are also familiar with assays and animal studies to assess whether E-selectin antagonists lack significant anticoagulant properties. For example, an assay that determines the time required to form a clot can be used to screen for or characterize the ability of an E-selectin antagonist to significantly slow clotting, in which case Drugs that have reduced ability to delay clotting, drugs that do not have this, or drugs that lack this are desired. As an example, the bleeding time may be assessed in rodents injected with a test E-selectin antagonist or control, and the bleeding time is recorded after the tail vein is injured and the tail is immersed in isotonic saline.

  Conditions for a particular assay include temperature, buffer (including salt, cation, medium), and other components and compounds that maintain the integrity of any cells used in the assay, and are known to those skilled in the art. If so, they are familiar and / or can be easily determined. One skilled in the art will also readily recognize that appropriate controls can be designed and included when performing the in vitro and in vivo methods described herein.

  The source of an agent described herein and characterized by one or more assays and techniques in the art may be a biological sample obtained from a subject treated with the agent. Cells that can be used in the assay may also be provided in a biological sample. A “biological sample” can include a sample from a subject, from which a blood sample (from which serum or plasma can be prepared), biopsy material, one or more bodily fluids (eg, lung lavage fluid, ascites, (Mucosal lavage fluid, joint fluid, urine), bone marrow, lymph node, tissue graft, organ culture, or any other tissue or cell preparation from a subject or biological source. A biological sample has a morphological integrity or physical state such as incision, dissociation, lysis, fractionation, homogenization, biochemical or chemical extraction, grinding, lyophilization, sonication, Or it can further mean a tissue or cell preparation that has been destroyed by any other means for processing samples from a subject or biological source. In certain embodiments, the subject or biological source is a human or non-human animal, primary cell culture (eg, immune cell), or cell line adapted for culture (including but not limited to a chromosome integrated). A genetically engineered cell line that can contain a nucleic acid sequence of episomal or episomal recombination; an immortalized or immortalizable cell line; a somatic cell hybrid cell line; a differentiated or differentiable cell line, trait Including transformed cell lines).

Exemplary animal models have been described herein and in the art to determine the effectiveness of E-selectin antagonists. A number of cancer animal models are routinely practiced in the art. As a non-limiting example, ALL, multiple myeloma, AML models, and solid tumor cancer models are available to determine the efficacy of E-selectin antagonists. Typically, an animal is transplanted with a tumor cell line (eg, but not limited to, pancreatic, breast, colon, ovarian, ALL, AML, multiple myeloma tumor cell lines) And / or after the tumor is established, administering the agent of interest. Numerous statistical analyzes are available and understood by those skilled in the art and may be applied to compare the effect of a drug with one or more appropriate controls.

Pharmaceutical Compositions and Methods of Use of Pharmaceutical Compositions Any one or more of the E-selectin antagonist agents described herein, eg, Formula I (and substructures and specifics thereof described herein) Also provided herein is a pharmaceutical composition comprising one or more of the structure) sugar mimetic compounds. The compounds, isolated antibodies, and other E-selectin antagonists described herein may also be tailored for pharmaceutical use in subjects, including human subjects. The compounds described herein are pharmaceutical compositions for use in treatment or prophylactic (or prophylactic) treatment (eg, reducing the likelihood of developing or exacerbating a disease or one or more symptoms of a disease). It may be formulated into a product. The methods and excipients described herein are exemplary and not limiting in any way.

  In a pharmaceutical dosage form, any one or more of the sugar mimetic compounds of Formula I, substructures and specific structures described herein are administered in the form of a pharmaceutically acceptable derivative, eg, a salt. Or they may be used alone or in appropriate combination and combination with other pharmaceutically active compounds. By way of example, as described herein with respect to methods of use, an E-selectin antagonist may be administered to a subject who is also receiving a combination of chemotherapy, radiation therapy, chemotherapy and radiation therapy.

  An effective amount or therapeutically effective amount is an amount of a glycomimetic compound, or a composition comprising one or more compounds; or one or more isolated antibodies (or other E-selectin antagonist agents), An amount effective to provide a desired therapeutic effect when administered to a subject either as a single dose or as part of a series of doses. The optimal dose can generally be determined using experimental methods and / or clinical trials. The design and execution of preclinical and clinical studies for each therapeutic agent described herein (including when administered for prophylactic legal benefits) is within the knowledge of one of ordinary skill in the relevant arts. is there. The optimal dose of the therapeutic agent may depend on the subject's body mass, weight or blood volume. In general, the amount of a compound described herein present in a dose ranges from about 0.01 μg to about 1000 μg per kg body weight of the host. In general, the amount of a polypeptide or peptide described herein or antibody or antigen-binding fragment thereof present in a dose will also range from about 0.01 μg to about 1000 μg per kg subject. It is usually preferred to use the lowest dose that is sufficient to provide effective therapy. In general, the subject may be monitored for therapeutic efficacy using an assay appropriate for the disease or condition being treated or prevented, and this assay is well known to those of skill in the art and is described herein. Yes. Said compound, peptide, antibody or antigen-binding fragment thereof in a biological fluid, such as in blood, blood fraction (eg, serum), and / or urine, and / or other biological sample from a subject. Alternatively, the level of a compound or polypeptide administered to a subject may be monitored by determining the level of the polypeptide (or any metabolite of the molecule). Any method practiced in the art for detecting the molecule may be used to measure the level of the molecule during a treatment regime.

The dose of the compound, peptide, antibody or antigen-binding fragment thereof, or polypeptide described herein is determined by the subject's symptoms, i.e. stage of the disease, severity of symptoms caused by the disease, general health condition, As well as age, gender and weight, and other factors apparent to those skilled in the medical arts. Similarly, the dose of a therapeutic agent for treating a disease or disorder may be determined according to parameters understood by those skilled in the medical arts.

  The pharmaceutical composition can be administered in a manner appropriate to the disease or disorder to be treated as determined by those skilled in the medical arts. The appropriate dosage and the appropriate duration and frequency of administration are factors including the patient's symptoms, the type and severity of the patient's disease, the specific form of the active ingredient and the method of administration, as discussed herein. Will be determined by. In general, appropriate doses (effective doses) and therapies can provide treatment and / or prophylactic benefits (eg, more frequent full or partial sedation, or disease free, as described in detail above) The pharmaceutical compositions described herein are provided in an amount sufficient to provide symptom and / or increased overall survival, or improved clinical outcome, such as reduced severity of symptoms.

  The pharmaceutical compositions described herein may be administered to a subject in need thereof by any one of several routes that effectively deliver an effective amount of the compound. Such administration routes include, for example, topical, oral, nasal, intrathecal, enteral, buccal, sublingual, transdermal, rectal, vaginal, intraocular, subconjunctival, sublingual, or parenteral (subcutaneous, Intravenous, intramuscular, intrasternal, intravenous, intrameal or intraurethral injection or infusion). Compositions administered by these routes of administration and the like are described in more detail herein.

  The pharmaceutical composition is a sterile aqueous solution further comprising a physiologically acceptable excipient (pharmaceutically acceptable or suitable excipient or carrier) (ie, a non-toxic substance that does not interfere with the activity of the active ingredient). Or it may be a sterile non-aqueous solution, suspension or emulsion. The composition may be in the form of a solid, liquid or gas (aerosol). Alternatively, the compositions described herein can be formulated as a lyophilizate, or the compounds and polypeptides or peptides described herein can be prepared using techniques known in the art. It can be encapsulated in liposomes. The pharmaceutical composition may also include other ingredients that may be biologically active or inactive. Such components include, but are not limited to, buffers (eg, neutral buffered phosphate or phosphate buffered saline), carbohydrates (eg, glucose, mannose, sucrose, or dextran), mannitol, proteins, polypeptides, or glycine. Amino acids, antioxidants, chelating agents such as EDTA or glutathione, stabilizers, dyes, fragrances, and suspending and / or preservatives.

Any suitable excipient or carrier known to those of skill in the art for use in pharmaceutical compositions can be employed in the compositions described herein. Excipients for therapeutic use are well known and are described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)). In general, the type of excipient is selected based on the mode of administration and the chemical composition of the active ingredient. For example, topical, oral, nasal, intrathecal, intestine, buccal, sublingual, transdermal, rectal, intravaginal, intraocular, subconjunctival, sublingual, or subcutaneous, intravenous, intramuscular, intrasternal, intracavity The pharmaceutical composition can be formulated according to any suitable mode of administration, including parenteral administration, including intraoral or intraurethral injection or infusion. For parenteral administration, the carrier preferably comprises water, saline, alcohol, a fat, a wax or a buffer. For oral administration, the above excipients, or mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, kaolin, glycerin, starch dextrin, sodium alginate, carboxymethylcellulose, ethylcellulose, glucose, sucrose and / or magnesium carbonate Solid excipients or carriers such as can be employed.

Pharmaceutical compositions (eg, for oral administration or delivery by injection) may be in liquid form. Liquid pharmaceutical compositions include, for example, sterile diluents such as water for injection, saline solutions, preferably physiological saline, Ringer's solution, isotonic sodium chloride, non-volatile oils that can function as solvents or suspending media, polyethylene glycol, Can include one or more of glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for tonicity adjustment such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Saline is suitable for use and injectable pharmaceutical compositions are preferably sterile.

  For oral formulations, at least one of the E-selectin antagonist agents described herein alone or suitable additives for making tablets, powders, granules or capsules, such as any one It can be used in combination with one or more conventional additives, degrading agents, lubricants, and optionally diluents, buffering agents, wetting agents, preservatives, coloring agents, and flavoring agents. The composition may be formulated to include a buffer to provide protection of the active ingredient from the low pH of the stomach environment, and / or an enteric coating. For oral delivery, for example, the composition may be formulated with a liquid, solid or semi-solid flavoring agent and / or with an enteric coating.

  Oral formulations can be provided as gelatin capsules which can contain the active compound or biological product with a powdered carrier. Similar tablets and diluents can be used to make compressed tablets. Tablets and capsules can be manufactured as sustained release products to allow for continuous release of active ingredients over a period of time. Compressed formulations can be sugar or film coated to mask unpleasant tastes and protect the tablet from the atmosphere or enteric coated for selective disintegration in the gastrointestinal tract.

  The pharmaceutical composition may be formulated for sustained or sustained release. In general, the compositions can be prepared using well-known techniques and administered, for example, by oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Sustained release formulations can include an active therapeutic agent dispersed in a carrier matrix and / or an active therapeutic agent contained within a reservoir surrounded by a rate controlling membrane. The excipient used in the formulation is biocompatible and may also be biodegradable. Preferably, the formulation releases the active ingredient at a relatively constant level. The amount of active therapeutic agent contained within the sustained release formulation will depend on the site of implantation, the rate and estimated duration of release, and the nature of the condition to be treated or prevented.

  The pharmaceutical compositions described herein can be formulated as suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. The pharmaceutical composition can be prepared as an aerosol formulation to be administered via inhalation. The composition can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane and nitrogen.

Any one or more of the E-selectin antagonist agents described herein can be administered locally (eg, by transdermal administration). Topical formulations may be in the form of transdermal patches, ointments, pastes, lotions, creams and gels. A topical formulation can include one or more penetrants, or enhancers (also referred to as penetration enhancers), thickeners, diluents, emulsifiers, dispersion aids, or binders. Physical penetration enhancers include, for example, electrophoretic techniques such as iontophoresis and the use of ultrasound (or “phonophoresis”). Chemical penetration enhancers enhance the permeability of the skin, especially the stratum corneum, and enhance the penetration of drugs through the skin, administered before, simultaneously with, or immediately after the administration of a therapeutic agent Is a drug. Additional chemical and physical penetration enhancers can be found, for example, in Transdermal Delivery of Drugs, A. et al. F. Ky
donieus (ED) 1987 CRL Press; Percutaneous Penetration Enhancers, eds. Smith et al. (CRC Press, 1995); Lenneras et al. Pharm. Pharmacol. 54: 499-508 (2002); Karande et al., Pharm. Res. 19: 655-60 (2002); Vaddi et al., Int. J. et al. Pharm. 91: 1639-51 (2002); Ventura et al., J. Biol. Drug Target 9: 379-93 (2001); Shokri et al., Int. J. et al. Pharm. 228 (l-2): 99-107 (2001); Suzuki et al., Biol. Pharm. Bull. 24: 698-700 (2001); Alberti et al., J. Biol. Control Release 71: 319-27 (2001); Goldstein et al., Urology 57: 301-5 (2001); Kiijavainen et al., Eur. J. et al. Pharm. Sci. 10: 97-102 (2000); and Tenjarla et al., Int. J. et al. Pharm. 192: 147-58 (1999).

  Kits comprising one or more unit doses (usually oral doses or injectable doses) of the compounds, polypeptides, peptides, aptamers, antibodies and antigen-binding fragments thereof described herein are provided. Such a kit comprises a container containing a unit dose, an information package explaining the use and associated benefits of the therapeutic agent in the treatment of a pathological condition of interest, and optionally for delivering the composition An instrument or device.

Example 1
Synthesis of E-Selectin Inhibitors Exemplary sugar mimetic compounds of formula I as described in this example and as illustrated in the exemplary synthetic schemes shown in FIGS. Was synthesized.

Synthesis of Compound 2: Compound 1 (60 g) was suspended in H ₂ O (800 ml) and cooled to 0 ° C. Solid NaHCO ₃ (120 g) was added in portions with stirring, then a solution of KI (474.3 g) and I ₂ (127 g) in H ₂ O (800 ml) was added with stirring. The reaction mixture was stirred in the dark at room temperature overnight. The reaction mixture was then extracted with CH ₂ Cl ₂ (3 × 500 ml). The organic layer was washed with Na ₂ S ₂ O ₃ solution ( ₂ × 500 ml) and then the combined aqueous layers were extracted with CH ₂ Cl ₂ ( ₂ × 300 ml). The organic layers (2100 ml) were combined and washed with cold H ₂ O (1 × 500 ml) and cold brine (1 × 500 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness to give compound 2 as pale yellow crystals (119 g). Purity:> 95% (by TLC).

Synthesis of Compound 3: To a solution of Compound 2 (119 g) in THF (1600 ml), DBU (119 ml) was added at room temperature with stirring, and the reaction mixture was refluxed gently overnight with stirring. Some precipitate formed and TLC showed no starting material left. The reaction mixture was concentrated to dryness, dissolved in EtOAc (300 ml) and washed with 0.5 M HCl (200 ml) to an aqueous wash of pH 2-3, then the organic layer was washed with H ₂ O (200 ml). Further washing was performed. The aqueous layers were combined and extracted with EtOAc (3 × 200 ml) to produce a second organic layer. The combined organic layers (900 ml) were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to dryness to give compound 3 (58 g). Purity:> 95% (by TLC).

Synthesis of Compound 4: To a solution of Compound 3 (58 g) in MeOH (800 ml), NaHCO ₃ (47 g) was added with stirring. The reaction mixture was stirred at gentle reflux for 3 hours, cooled to room temperature, filtered and concentrated to dryness. The residue was dissolved in EtOAc (300 ml) and washed with H ₂ O. The aqueous layer was extracted with EtOAc (3 × 100 ml). Combined organic layers (600
ml) was washed with 0.5M HCl (200 ml), H ₂ O (100 ml), and brine (100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to dryness. Column chromatography (SiO _2, hexane -EtOAc3: 1 → 3: 2) to give a residue, to give compound 4 (54 g). Purity:> 95% (by TLC).

  Synthesis of Compound 5: Compound 4 (31 g) was dissolved in tBuOMe (620 ml) and vinyl acetate (166 ml) was added with vigorous stirring. Novozyme 435 (1.4 g) was added and vigorous stirring continued for 5.5 hours. The reaction mixture was filtered and stored at -20 ° C. After 12-18 hours, another batch of Novozyme 435 resin (1.4 g) was added and stirred vigorously for 8 hours. The resin was filtered and concentrated to dryness. The oily residue was purified by CombiFlash® system (silica) using 0 → 50% EtOAc / hexane to give compound 5 (13.0 g).

Synthesis of Compound 6: Compound 5 (13.5 g) was dissolved in CH ₂ Cl ₂ (300 ml) under argon and TBDMS-Cl (26.4 g) was added with stirring at room temperature under argon. DBU (32.4 ml) was added and stirring was continued overnight at room temperature under argon. MeOH (30 ml) was added and washed with cold saturated NaHCO ₃ solution (200 ml) and brine (150 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to dryness. The residue was purified by CombiFlash® system (SiO ₂ ) using EtOAc-hexane (0-15%) solvent to give compound 6 (18 g). Purity> 95% (according to TLC).

Synthesis of Compound 7: Compound 6 (12 g) was dissolved in CH ₂ Cl ₂ (400 ml) and cooled to 0 ° C. Additional m-chloroperbenzoic acid (77%, 19 g) was added and the solution was stirred for several hours during which time the temperature of the reaction mixture reached room temperature. Stirring was continued overnight at room temperature. Added CH ₂ Cl ₂ (300 ml), washed with cold saturated NaHCO ₃ solution ( ₃ × 400 ml), brine (cold), dried (Na ₂ SO 4), filtered and concentrated to dryness. The residue was purified by CombiFlash® system (SiO ₂ ) using EtOAc-hexane (0 → 30%) to give 7 (9 g). Purity:> 95% (by TLC).

Synthesis of Compound 8: All operations in this step were performed under an argon atmosphere. CuCN (9.42 g) was dried under vacuum at 160 ° C. for 40 minutes, cooled to room temperature, and suspended in THF (80 ml). The mixture was cooled to -78 ° C. During this time, tetravinyltin (12 ml) and n-BuLi hexane solution (2.5 M, 100 ml) were reacted at 0 ° C. for 30 minutes in THF (30 ml). This solution was added to a THF mixture of CuCN and the resulting mixture was stirred at −20 ° C. for 30 minutes. The mixture was then cooled to −78 ° C. and freshly distilled BF ₃ . Et2O (6 ml) in THF (20 ml) was added to this. The mixture was stirred at −78 ° C. for 20 minutes. A solution of compound 7 (5 g) in THF (40 ml) was added and the reaction mixture was stirred at −78 ° C. for 5 hours. MeOH (7 ml) and Et ₃ N (3 ml) were added and the mixture was concentrated to dryness. The residue was dissolved in EtOAc (200 ml), washed with saturated NaHCO ₃ solution (2 × 100 ml), brine (100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to dryness. The residue was purified by CombiFlash® system (SiO ₂ ) using EtOAc-hexane (0 → 5%) solvent to give compound 8 (2.5 g).

Synthesis of compound 10: Compound 8 (2.25 g, 7 mmol) was dissolved in toluene (7 ml) and the solvent was evaporated. This process was repeated twice and finally dried under vacuum for 15 minutes. The residue was dissolved in anhydrous CH ₂ Cl ₂ (45 ml) and DMF (45 ml) was added. This solution was stirred at room temperature under argon, and a molecular sieve (3 g, 4 kg, powder-dried) was added. Et ₄ NBr (3.3 g, 15.7 mmol, 2.2 eq, dried at 200 ° C. for 2 hours) was added and stirring was continued for 1 hour at room temperature under argon.

Compound 9 (5.13 g, 10 mmol, 1.42 eq) was coevaporated with toluene (3 × 20 ml), dried under vacuum and dissolved in CH ₂ Cl ₂ (45 ml). The reaction mixture was placed in an ice bath and stirred for 10 minutes. In an ice bath, Br ₂ (0.8 ml, 15 mmol, 1.5 eq) was added dropwise to the solution with stirring. Stirring was continued for 40 minutes at the same temperature. The ice bath was removed and after 10 minutes cyclohexene (2.1 ml) was added slowly with stirring. The reaction mixture was stirred for 10 minutes and added slowly to the reaction mixture with stirring at room temperature under argon. Stirring was continued for 17 hours, then pyridine (4 ml) was added and filtered, and the filtrate was concentrated to dryness. The residue was dissolved in CH ₂ Cl ₂ (100 ml) and transferred to a separatory funnel. The organic layer was washed with cold brine (2 × 75 ml), dried (Na ₂ SO ₄ ), filtered, concentrated to dryness, coevaporated with toluene (3 × 50 ml) and dried under vacuum. The residue was dissolved in THF (8 ml) and TBAF (1M in THF, 10 ml, 10 mmol, 1.42 equiv) solution was added at room temperature with stirring. Stirring was continued for 15 hours and the solvent was evaporated. The residue was dissolved in CH ₂ Cl ₂ (100 ml), transferred to a separatory funnel, washed with cold brine (2 × 75 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to dryness. The residue was purified by column chromatography (hexane-ethyl acetate, 100% hexane to 70% hexane EtOAc solution) to give compound 10 (1.6 g, 2.59 mmol, 37% over 2 steps). TLC: 5% EtOAc in hexane and 33% EtOAc in hexane.

Synthesis of compound 12: Commercial compound 11 (10 g) was dried under vacuum overnight and added to a solution of NaOMe (5 M, 10 ml) in MeOH (200 ml) with stirring at room temperature under argon. Stirring was continued overnight at room temperature under argon, and Et ₃ N (7 ml) was added dropwise followed by allyl chloroformate (3.5 ml). Stirring was continued for 6 hours at room temperature under argon. The reaction mixture was concentrated to dryness and dissolved in pyridine (100 ml). Ac ₂ O (50 ml) was added at room temperature under argon and stirred at room temperature overnight. The reaction mixture was concentrated to dryness and purified by column chromatography on a CombiFlash® system using EtOAc-hexane (0-100%). The desired fractions were collected and concentrated to dryness to give compound 12 (10.2 g).

Synthesis of Compound 13: Compound 12 (7.5 g) was dissolved in DMF (140 ml) and NH ₄ OAC (4.05 g) was added to it with stirring. Stirring was continued overnight at room temperature under argon. The next day, the reaction mixture was stirred at 50 ° C. under argon for 8 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (150 ml), washed with brine (100 ml), dried (Na ₂ SO 4), filtered and concentrated to dryness. The residue was purified by column chromatography (SiO2, hexane-EtOAc ₂ : 1 → 1: 2) to give compound 13 (6 g).

Synthesis of Compound 14: Compound 13 (6 g) was dissolved in CH ₂ Cl ₂ (50 ml) and CCl ₃ CN (6 ml) and DBU (0.5 ml) were added thereto. The reaction mixture was stirred at room temperature for 0.5 h, the solvent was evaporated and the residue was purified by column chromatography (silica gel) to give compound 14 (4.5 g).

Synthesis of Compound 15: Compound 10 (2 g) and Compound 14 (2.1 g) were dissolved in CH ₂ Cl ₂ (40 ml). To this solution, molecular sieve (4 kg, 0.8 g) was added and stirred at room temperature for 30 minutes. The solution was then cooled to 0 ° C. and BF ₃ Et ₂ O (0.25 ml dissolved in 5 ml) was added with stirring at 0 ° C. The reaction mixture was stirred at 0 ° C. for 2 hours. Et ₃ N (0.5 ml) was added and the solvent was evaporated. The residue was purified by column chromatography (silica gel) to give compound 15 (1.8 g).

Synthesis of Compound 16: Compound 15 (1.7 g) was treated with 0.01 N NaOMe in MeOH (10 ml) for 2 hours, neutralized with IR-120 (H ⁺ ) resin, filtered and concentrated to dryness. Compound 16 (1.25 g) was obtained.

Synthesis of Compound 17: Et3N (0.28 ml) was added to a solution of Compound 16 (1.2 g) in CH ₃ CN (30 ml) and cooled to 0 ° C. To this solution, BzCN (0.35 mg dissolved in 10 ml of CH ₃ CN) was added dropwise at 0 ° C. for 20 minutes. The reaction mixture was stirred at 0 ° C. for 1 hour and concentrated to dryness. The residue was purified by column chromatography (silica gel) to give compound 17 (0.95 g).

Synthesis of Compound 19: Compound 17 (0.9 g) was dissolved in MeOH (12 ml). To this solution was added Bu ₂ SnO (0.4 g) and the mixture was refluxed for 2 hours. The solvent was evaporated and the remaining solvent was coevaporated 3 times with toluene. The residue was dissolved in dimethoxyethane (15 ml). To this solution was added CsF (0.8 g) and compound 18 (2.1 g, synthesized as previously described in J. Med. Chem. 42: 4909, 1999). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated. The residue was purified by column chromatography to give compound 19 (0.8 g).

Synthesis of Compound 20: Compound 19 (0.7 g) was dissolved in CH ₂ Cl ₂ (20 ml). To this solution was added Pd (Ph) ₄ (0.14 g), Bu ₃ SnH (0.15 ml), and Ac ₂ O (0.3 ml), and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by column chromatography (silica gel) to give compound 20 (0.5 g).

Synthesis of Compound 21: 10% Pd—C (0.15 g) was added to a solution of Compound 20 (0.45 g) in dioxane-H ₂ O—AcOH (10: 2: 1, 2.6 ml) and the reaction mixture was Shake for 5 hours at room temperature under positive hydrogen pressure (20 psi). The solid was removed by filtration and the filtrate was concentrated to dryness. The residue was purified by column chromatography (silica gel) to give compound 21 (0.3 g).

  Synthesis of Compound 22: Compound 21 (0.28 g) was treated with 0.025N NaOMe in MeOH (5 ml) for 4 hours, neutralized with IR-120 (H +) resin, filtered, and the filtrate was concentrated to dryness. Compound 22 (0.21 g) was obtained.

  Synthesis of Compound 23: Compound 22 (0.18 g) was dissolved in ethylenediamine (2 ml) and stirred at 80 ° C. for 8 hours. The solvent was evaporated and the residue was purified using a Sep-pak C18 cartridge to give compound 23 (0.15 g).

  Synthesis of compound 25: Compound 23 (200 mg) was dissolved in 1 mL of DMF. To this solution was added commercially available compound 24 (400 mg). Triethylamine (100 μL) was added dropwise to the reaction mixture to adjust the pH to 10. The reaction mixture was stirred at room temperature for 1 hour. After evaporation to dryness, the residue was purified by HPLC to give compound 25 (200 mg). See FIG. 1D.

Synthesis of compound 45: Compound 25 (300 mg) was dissolved in 3 mL of DMF. Diisopropylethylamine (60 μL) and HATU (131 mg) were added at room temperature. After stirring for 5 minutes, dimethylamine (2.3 mL, 2M THF solution) was added dropwise. The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in water and loaded onto a 10 g C-18 cartridge. Elution with water followed by 1/1 water / MeOH gave compound 45 (100 mg). Calculation of C ₆₂ H _{11 4} N ₄ O ₂₆ m / z = 1330
. 8. Found = 1353.6 (M + Na). ¹ H NMR 400 MHz (D ₂ O, set to 4.80 ppm) δ0.87 (t, J = 7.6 Hz, 3H), 0.94-0.99 (m, 2H), 1.20-1.25 (m, 4H), 1.25 (d, J = 6.4Hz, 3H), 1.26-1.45 (m, 4H), 1.52-1.73 (m, 6H), 1.79-1.88 (m, 3H), 2.00 (s, 3H), 2.11-2.19 (br d, 1H ), 2.33 (tt, J = 12.4Hz, J = 3.2Hz, 1H), 2.53 (t, J = 6.4Hz, 2H), 2.95 (s, 3H), 3.06 (s, 3H), 3.28 (t, J = 12.5Hz, 1H), 3.31-3.38 (m, 8H), 3.51-3.54 (m, 2H), 3.61 (dd, J = 8.0Hz, J = 0.8Hz, 1H), 3.63 (dd, J = 8.0Hz , J = 2.0Hz, 1H), 3.70 (s, 44H), 3.73-3.76 (m, 1H), 3.78 (t, J = 6.0Hz, 1H), 3.81-3.82 (m, 1H), 3.88 (dd, J = 8.0Hz, J = 3.6Hz, 1H), 3.99 (bs, 1H), 4.54 (dd, J = 8.8Hz, J = 2.0Hz,
2H), 4.91 (q, J = 6.8Hz, 1H), 5.04 (d, J = 3.6Hz, 1H).

  Synthesis of Compound 26: as described for Compound 25, except that the n of the PEG reactant was 8 (ie, 8 repeating PEG units) instead of 12 as in Compound 25 synthesis. (See FIG. 1D), compound 26 was synthesized.

Calculated for C ₅₂ H ₉₃ N ₃ O ₂₃ m / z = 1127.6. Found = 1151.6 (M + Na). ¹ HNMR 600 MHz (D ₂ O, set to 4.67 ppm) d 0.71 (t, J = 7.2 Hz, 3H), 0.76 (br quin, J
= 12.0Hz, 2H), 0.99-1.06 (m, 4H), 1.08 (d, J = 6.6Hz, 3H), 1.15-1.19 (br quin, J
= 6.6Hz, 1H), 1.21-1.25 (m, 2H), 1.39-1.48 (m, 5H), 1.50-1.60 (m, 3H), 1.70 (brd, J = 10.2Hz, 2H), 1.91 (s, 3H), 1.99 (m, 1H), 2.16 (br t, J = 12.6Hz, 1H), 2.36
(t, J = 6Hz, 2H), 3.11-3.15 (m, 2H), 3.18 (t, J = 9.6Hz, 3H), 3.22 (s, 3H), 3.38
(dd, J = 7.8Hz, J = 4.2Hz, 2H), 3.46 (dd, J = 4.2Hz, 1H), 3.47 (s, 1H), 3.52-3.55 (m 27H), 3.56-3.59 (m, 3H ), 3.61-3.64 (m, 3H), 3.65 (d, J = 3.6Hz, 1H), 3.72 (dd, J = 10.2Hz, J = 3.0Hz, 1H), 3.80 (d, J = 2.4Hz, 1H ), 3.85 (br s, 1H), 3.94 (dd, J = 9.6Hz, J = 3.6Hz, 1H), 4.36 (br s, 1H), 4.77 (q, J = 6.6Hz, 1H), 4.88 (d , J = 4.2Hz, 1H).

  Synthesis of Compound 27: Compound 27 was synthesized as described in FIG.

Synthesis of Compound 27A: Compound 19 (0.05 g) was dissolved in CH ₂ Cl ₂ (10 ml). To this solution, Pd [(Ph ₃ ) P] ₄ (5 mg), Bu3SnH (0.0011 ml)
And _(CF3CO) 2 O _(0.0015ml) was added with stirring at room temperature. Stirring was continued for 30 minutes at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (silica gel) to give compound 27A (0.030 g).

In exactly the same manner as described for compound 21, compound 27A (0.025 g) was hydrogenated with 10% Pd-C, the catalyst was filtered off and the solvent was evaporated. The residue was treated with NaOMe in MeOH, neutralized with IR-120 (H +) resin, filtered and the solvent was evaporated as described for compound 22. The residue was purified by reverse phase (C18) HPLC to give compound 27 (7 mg). Calculation of C ₃₃ H ₅₂ F ₃ NO ₁₅ m / z = 759.3. Found = 782.3 (M + Na).

  Synthesis of compound 28:

Synthesis of Compound 28: Commercially available compound 27B (0.014 g) was dissolved in DMF (1 ml). To this solution was added DIPEA (0.00175 ml) and HATU (0.038 g) and the reaction mixture was stirred at room temperature for 2 minutes. Compound 23 (0.035 g) was added and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by HPLC (C18) to give compound 28 (17 mg).

  Synthesis of compound 29:

In exactly the same manner as described for compound 28, commercially available compound 27C (0.021 g) was reacted with compound 23 (0.035 g) and purified by HPLC (C18) to give compound 29 (0.020 g). )

Example 2
E-Selectin Activity-Binding Assay Inhibition assays that screen and characterize glycomimetic E-selectin antagonists are competitive binding assays that allow determination of IC ₅₀ values. E-selectin / Ig chimeras were immobilized in 96-well microtiter plates by incubating at 37 ° C. for 2 hours. To reduce non-specific binding, bovine serum albumin was added to each well and incubated for 2 hours at room temperature. Plates were washed and serial dilutions of test compounds were added to the wells in the presence of ^a biotinylated sLea polyacrylamide and streptavidin / horseradish peroxidase conjugate and incubated for 2 hours at room temperature.

To determine the amount of sLe ^a binding to immobilized E- selectin after washing, peroxidase substrate 3,3 ', 5,5' added a tetramethylbenzidine (TMB). After 3 minutes, the enzymatic reaction was stopped by the addition of H ₃ PO ₄ and the light absorbance at a wavelength of 450 nm was determined. The concentration of test compound required to inhibit binding by 50% was determined and reported as the IC ₅₀ value for each glycomimetic E-selectin antagonist as shown in the table below. IC ₅₀ values for exemplary compounds disclosed herein are shown in the following table.

In addition to reporting the absolute IC ₅₀ value measured above, the relative IC ₅₀ value (rIC ₅₀ ) is determined by the ratio of the IC ₅₀ measured for the test compound to that of the internal control (reference) described for each assay.

Replacing the methyl group at the R ³ position of compound 22 with a trimethylfluoro (—CF ₃ ) group did not significantly change the E-selectin antagonist activity of compound 22; Was significantly increased, thereby improving the bioavailability of the sugar mimetic compound.

Example 3
Effect of E-selectin specific antagonist (compound 25) treatment in leukemia animal model The E-selectin ligand HCELL (hematopoietic cell E- / L-selectin ligand) is expressed by normal hematopoietic stem cells as a functional CD44 glycoform. (Merzaban et al., Blood 118 (7): 1774-83 (2011)). High levels of CD44 expression (99% ± 1.4%) are also blasts from 55 patients with acute myeloid leukemia (AML) (ie, AML blasts), and putative CD34 ⁺ CD38 ⁻ CD123 ⁺ leukemia Observed in stem cells (LSC) (99.8% ± 0.6%). The mean fluorescence intensity (MFI) of CD44 expression by AML blasts was 1-2 log higher than the MFI of the 16 other adhesion reporters. The majority of blasts from patients with AML also express E-selectin ligand according to flow cytometry: more than 75% of the 22 major gated blast samples average 22.7% ± 0.17 % SD, in the range of 1.8-66.2%, shows 10% or more binding of E-selectin-IgG chimeric protein. Immunoprecipitated CD44 from AML cell membrane, followed by sialyl Le ^a and sialyl Le ^x recognizes the functional trisaccharide domains that share, to bind to E- selectin stained with known HECA452 antibodies, the The ligand was identified as HCELL. HECA452 detected a functional CD44 glycoform (major E-selectin ligand) known as HCELL and also identified the human lymphocyte homing receptor CLA (skin lymphocyte antigen).

HECA452 labeled 5 out of 6 patient leukemia blast populations with an average expression of 59.0% ± 24.8%. The HECA452 antibody labeled CD34 ⁺ CD38 ⁻ CD123 ⁺ LSC in addition to leukemic blasts with a higher percentage of expression than the corresponding unfractionated blast population in most LSC cases. HECA452 also labeled 94% of human AML cells (scid regrowth cells) serially transplanted into NODscid IL2Rgc ^{− / −} animals that meet the functional definition of LSC, indicating that HCELL is abundant on LSC It suggests. When cells bound to E-selectin-coated plastic, AML blast morphological changes were observed. In contrast to non-adherent cells that were still round and refractive, AML blasts became elongated, more cubic and less reflective. AML blasts appear to bind to the elongated ends of spindle-shaped endothelial cells. Compound 25 (concentration 20 μM) inhibited, on average, 45.0% ± 9.1% SD of primary human AML cells from adhering to E-selectin for samples from all patients. For example, in some patients, the inhibition rate by Compound 25 compared to vehicle control was 33.4% ± 15.3% SD, p = 0.000018.

Adhesion to E-selectin did not result in the adhesion-mediated chemotherapy resistance to daunorubicin or cytarabine observed with adhesion to recombinant fibronectin peptide or immobilized VCAM-1 (Becker et al., Blood 113 (4): 866-74. (See 2009). We have a dual inhibitor of E-selectin and CXCR4 glycomimetic compounds (see US Patent Application Publication No. 2010/0279965), where we have the CXCR4 inhibitor prelixafor ( Chien et al., Abstract 1432, at American Society for Hematology, 53 rd ASH Annual Meeting and Exposition, San Diego, CA; a see December 10-13,2011) large than was observed alone, NODscid IL2Rgc ^{- / -} mice (Chien et al., Abstract 579, at American Society for Hematology, 53 rd ASH Annual Meeting and E position, San Diego, CA; December 10-13,2011; Blood, demonstrated the (3-4-fold to about 2 times that mobilized human AML transplanted to) see Volume 118, Issue 21). In immunodeficient xenograft mice transplanted with human AML, E-selectin antagonist compound 25 (40 mg / kg) mobilized both human and mouse cells. At 3 hours, a 2-fold increase in WBC (p = 0.00067) and a 2-fold increase in human AML cells (p = 0.14) were observed.

  In another experiment, human AML blasts were transplanted into mice and treated with Compound 25 in combination with daunorubicin and cytarabine (araC) or with daunorubicin and cytarabine alone. Mice were treated when AML cells contained approximately 10% of blood cells. On day 1, day 2 and day 3, compound 25 was administered twice daily at 40 mg / kg to a group of animals (4 per group). On day 1, daunorubicin (3 mg / kg) and araC (300 mg / kg) were administered 3 hours after the animals were first treated with compound 25. On days 2 and 3, only araC (300 mg / kg) was administered 3 hours after the initial administration of Compound 25. Compound 25 and chemotherapeutic drugs were administered intraperitoneally. Group 2 mice received daunorubicin and araC only. Tumor burden was measured in bone marrow, blood, and spleen.

  The combination of Compound 25 and the two chemotherapeutic agents is larger than that observed with daunorubicin and cytarabine in the absence of Compound 25, bone marrow (22% AML cells) and spleen (31% AML cells) Caused depletion of human AML. Without being bound by any particular theory, it is possible that E-selectin may be involved in the presence of human AML in the myeloid vascular niche, and the AML blast migration may interact with the vascular endothelium via E-selectin. Action may be involved. See Chien et al., Poster 4092 at American Society for Hematology, 54th ASH Annual Meeting and Exposure, Atlanta, GA Decemer, 8-11, 1012; Blood, Vol.

Example 4
Effect of E-Selectin Specific Antagonist Treatment in Acute Lymphoblastic Leukemia (ALL) Animal Model The efficacy of an E-selectin antagonist in an ALL animal model is determined. Experiments are designed according to methods routinely practiced in the art with respect to selection of ALL cell lines, number of animals per group, test group and control dosing and dosing schedules, and statistical analysis methods. For example, ALL Namm-6 cells are tagged with green fluorescent protein (GFP) or DiD (carbocyanine fluorescent dye) and then transplanted into mice (1 × 10 ⁶ cells per mouse). Approximately one week after the tagged cells are administered to animals, groups of mice (6 per group) are treated as follows. The first group (control) receives only vehicle (PBS). Each animal in the second group receives an E-selectin antagonist (eg, compound 25 (40 mg / kg)) daily on days 1, 2, and 3. A third group of animals receives a chemotherapeutic drug (eg, doxorubicin (DOX) (2 mg / kg)) daily on days 1, 2 and 3 (referred to as dose 1). Group 4 mice are each administered Compound 25 (40 mg / kg) once daily on Days 1, 2, and 3 three hours prior to DOX administration (2 mg / kg). Group 5 is administered DOX daily at days 1, 2 and 3 at a dose of 3 mg / kg (referred to as administration 2). In Group 6, each animal receives Compound 25 (40 mg / kg) once daily on Days 1, 2 and 3 3 hours prior to DOX administration (3 mg / kg). Mice are observed for up to 2 months. During the observation period, the survival, circulating leukemia cells, and leukemic burden in the bone marrow are determined. Circulating leukemia cell numbers are determined by in vivo flow cytometry. Biomicroscopy is performed to determine the leukemia load in the bone marrow.

Example 5
Effect of E-selectin specific antagonist treatment in a pancreatic cancer animal model The efficacy of an E-selectin antagonist in a pancreatic cancer animal model is determined. Male athymic nu / nu mice (4-6 weeks old) are injected in situ with S2.013 pancreatic cancer cells. From about 7 days after the injection of pancreatic cancer cells, six groups of animals (eg, 15 mice per group) receive the following treatment. Alternatively, animals are treated when a small tumor becomes perceptible. The first group (control) receives only vehicle (PBS). Group 2 is administered gemcitabine twice a week (2 / week) for 4 weeks. Group 3 is administered an E-selectin antagonist (eg, Compound 25 (40 mg / kg)) twice daily (BID) for 4 weeks. Group 4 is administered Compound 25 (40 mg / kg) once daily (qD) for 4 weeks. Group 5 is administered gemcitabine in combination with Compound 25 twice daily (BID). Group 6 is administered gemcitabine (administered twice daily for 4 weeks) in combination with compound 25 (administered once daily). Tumor burden is determined by ultrasound imaging or 2-deoxyglucose (2DG) imaging. Approximately 4 weeks after treatment, the animals are sacrificed.

Example 6
Efficacy of E-Selectin Specific Antagonist (Compound 25) Treatment in Venous Thromboembolism (VTE) Animal Model Animal Model Most venous thromboembolism animal models do not test compounds under continuous blood flow, but ligation or Thrombosis is induced by balloon catheterization. More clinically relevant models have been developed that temporarily induce damage under continuous blood flow and exposure to circulating test compounds at normal blood levels (eg, Diaz et al., Thromb. Haemot. 104: 366). 375 (2010)). A microelectrode is implanted in the inferior vena cava and a current of 250 uAmp is applied for 15 minutes. Typical endothelial dysfunction seen in venous disease was demonstrated by electron microscopy, immunohistochemistry, inflammatory cell counts, and thrombosis biomarkers. Ultrasound imaging further detected thrombus formation in real time under blood flow (see, eg, Diaz et al., Supra).

  Male C57BL / 6J mice were subjected to an electrolytic vena cava (lVC) model to create non-occlusive thrombus by electrical stimulation (250 μAmp). Animals were divided into prevention or treatment groups. Both groups included: non-thrombotic animals (TC, non-surgical or drug), 2 days sham (needle stimulation and non-current or drugs within IVC), 2 days CTR (non- Treatment: current and non-drug), 2 days of compound 25 (10 mg / kg, intraperitoneal (IP), twice daily (BID)), and low molecular weight heparin (LMWH) (LOVENOX®, 6 mg / kg) , Subcutaneous, once daily). Animals were divided into prevention or treatment groups. Mice in the prevention group were dosed from day 1 to day 1 before thrombus induction. The mice in the treatment group received the first drug administration after day 1 thrombus induction. Mice were euthanized 2 days after thrombosis for tissue collection and blood collection to evaluate: thrombus weight; venous wall inflammatory cell count / high power field; venous wall thrombohistology; and The number of polymorphonuclear cells (PMN) in the thrombus. In order to assess tail bleeding time (seconds), another group of mice received intravenous (IV) administration of the compound.

  In the electrolytic vena cava model (EIM), thrombus was induced in the inferior vena cava of mice as described above. After injury, E-selectin specific antagonist compound 25 (Example 1) was administered at 10 mg / kg as a twice daily treatment. Another cohort of mice received low molecular weight heparin (LMW heparin) (Lovenox, once daily, 6 mg / ml). As described above, on the second day after thrombus induction, the inferior vena cava was removed and weighed. Control mice did not receive electrodes. In the inferior vena cava of sham cohort mice, electrodes were implanted but no current was delivered. As shown in FIG. 4, treatment with 10 mg / kg of Compound 25 after injury resulted in significant venous thrombus formation, similar to LMW heparin (LMW heparin vs untreated, P = 0.0203). (Compound 25 vs. untreated, P = 0.0271). At 2 days after injury, all mice prophylactically pretreated with Compound 25 or LMWH followed the same thrombus weight reduction pattern (P <0.05).

Example 7
Effect of Compound 25 on the time required for clot formation To compare the anticoagulant properties of LMW heparin (LMWH) and Compound 25 (see Example 1), bleeding time in mice was evaluated. The test compound was injected through the penile vein of the mouse and after 5 minutes the tail vein was injured with a scalpel. The tail was then placed in a tube of isotonic saline and the time required for wound clotting was recorded.

  LMW heparin is a known anticoagulant. As shown in FIG. 5, LMW heparin delayed clotting more than 4 times longer than the control bleeding time, whereas compound 25 slightly delayed clotting. The 6 mg / kg dose of LMWH significantly increased tail bleeding time in mice compared to controls (341 ± 27, 491 ± 60 vs 82 ± 6 seconds, P <0.01). Compound 25 (10 mg / kg, intravenous (IV)) had significantly less tail bleeding time compared to intravenous (IV) administration of LMWH (6 mg / kg, P <0.01). Compound 25 significantly improves bleeding time reduction over LMW heparin.

  Venous wall morphometry and histology: In mice treated with Compound 25 after injury, monocyte emigration from the venous wall was significantly reduced compared to controls (P <0.05). Treatment of animals with Compound 25 or LMWH prophylactically (ie, before injury) significantly reduced PMN emigration from the venous wall observed 2 days after thrombosis (P = 0.027 and respectively). P = 0.007). For monocyte emigration from the venous wall at the same time point, the same pattern was applied in the case of prophylaxis with Compound 25 and LMWH (P <0.01).

  Intrathrombotic PMN: administration of Compound 25 as a prophylactic treatment significantly reduced the intrathrombotic cell count compared to control animals (14.5 ± 3.7 vs. 37.4 ± 4.7 PMN / HPF). , P = 0.009), the venous thrombosis decreased in these animals. Only mice treated with Compound 25 had more intra-thrombus vascular channels than control and LMWH treated mice.

  The various above embodiments can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, non-U.S. Patents, non-US patent applications, and non-patent publications mentioned in this specification and / or listed in the application are in their entirety. Which is incorporated herein by reference. If necessary, aspects of the embodiments can be modified to provide further embodiments to use various patent, application and publication concepts.

  These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terminology used should not be construed as limiting the claim to the specific embodiments disclosed in the specification and the claims, and thus It should be construed to include all possible embodiments in addition to the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

According to a preferred embodiment of the present invention, for example, the following is provided.
(Claim 1)
  Formula (I):

Or a pharmaceutically acceptable salt, isomer, tautomer, hydrate, or solvate thereof, wherein:
  R ¹ Is C ₁ -C ₈ Alkyl, C ₂ -C ₈ Alkenyl, C ₂ -C ₈ Alkynyl, C ₁ -C ₈ Haloalkyl, C ₂ -C ₈ Haloalkenyl or C ₂ -C ₈ Haloalkynyl;
  R ² Is H, or a non-sugar mimetic moiety or a linker-non-sugar mimetic moiety, wherein the non-sugar mimetic moiety is polyethylene glycol, thiazolyl, chromenyl, —C (═O) NH (CH ₂ ) _1-4 NH ₂ , C ₁ -C ₈ Alkyl, and -C (= O) OY (where Y is C ₁ -C ₄ Alkyl, C ₂ -C ₄ Alkenyl or C ₂ -C ₄ Is alkynyl);
R ³ Is C ₁ -C ₈ Alkyl, C ₂ -C ₈ Alkenyl, C ₂ -C ₈ Alkynyl, C ₁ -C ₈ Haloalkyl, C ₂ -C ₈ Haloalkenyl, C ₂ -C ₈ Haloalkynyl or cyclopropyl;
  R ⁴ Is —OH or —NZ ¹ Z ² (Where Z ¹ And Z ² Are independently H, C ₁ -C ₈ Alkyl, C ₂ -C ₈ Alkenyl, C ₂ -C ₈ Alkynyl, C ₁ -C ₈ Haloalkyl, C ₂ -C ₈ Haloalkenyl or C ₂ -C ₈ Haloalkynyl or Z ¹ And Z ² Combine to form a ring);
  R ⁵ Is C ₃ -C ₈ Is cycloalkyl;
  R ⁶ Are —OH, C ₁ -C ₈ Alkyl, C ₂ -C ₈ Alkenyl, C ₂ -C ₈ Alkynyl, C ₁ -C ₈ Haloalkyl, C ₂ -C ₈ Haloalkenyl or C ₂ -C ₈ Haloalkynyl;
  R ⁷ Is -CH ₂ OH, C ₁ -C ₈ Alkyl, C ₂ -C ₈ Alkenyl, C ₂ -C ₈ Alkynyl, C ₁ -C ₈ Haloalkyl, C ₂ -C ₈ Haloalkenyl or C ₂ -C ₈ Haloalkynyl; and
  R ⁸ Is C ₁ -C ₈ Alkyl, C ₂ -C ₈ Alkenyl, C ₂ -C ₈ Alkynyl, C ₁ -C ₈ Haloalkyl, C ₂ -C ₈ Haloalkenyl or C ₂ -C ₈ A compound, or a pharmaceutically acceptable salt, isomer, tautomer, hydrate, or solvate thereof, which is haloalkynyl.
(Section 2)
  (A) R ¹ , R ³ , R ⁶ , R ⁷ And R ⁸ At least one of C ₁ -C ₈ Is haloalkyl; (b) R ³ , R ⁶ , R ⁷ And R ⁸ At least one of C ₁ -C ₈ Is haloalkyl; (c) R ¹ , R ³ , R ⁶ , R ⁷ And R ⁸ At least two of C ₁ -C ₈ Is haloalkyl; (d) R ² Is a linker-non-sugar mimetic moiety; or (e) R ¹ , R ³ , R ⁶ , R ⁷ And R ⁸ At least one of C ₁ -C ₈ Haloalkyl and R ² The compound of claim 1, wherein is a linker-non-sugar mimetic moiety.
(Section 3)
  Each C ₁ -C ₈ Haloalkyl is —CH ₂ X, CH ₂ -(CH ₂ ) _m -CH ₂ X, CHX ₂ , -CH ₂ -(CH ₂ ) _m -CHX ₂ , -CX ₃ And -CH ₂ -(CH ₂ ) _m -CX ₃ Item 3. The compound according to Item 1 or 2, wherein m is 0 to 6, and X is F, Cl, Br, or I.
(Claim 4)
  Item 4. The compound according to Item 3, wherein at least one X is F.
(Section 5)
  At least one C ₁ -C ₈ Haloalkyl is —CH ₂ X, -CHX ₂ Or -CX ₃ Item 4. The compound according to Item 3, wherein
(Claim 6)
  Item 6. The compound according to Item 5, wherein X is F.
(Claim 7)
  R ⁴ Is —OH or NZ ¹ Z ² (Where Z ¹ And Z ² Respectively, C ₁ -C ₈ The compound according to any one of Items 1 to 3, which is alkyl).
(Section 8)
  Z ¹ And Z ² Are each -CH ₃ Item 8. The compound according to Item 7, wherein
(Claim 9)
  R ⁷ Is -CH ₂ OH, C ₁ -C ₈ Alkyl or C ₁ -C ₈ Item 9. The compound according to any one of Items 1 to 8, which is haloalkyl.
(Section 10)
  R ⁷ Is -CH ₂ OH or -CHF ₂ Item 10. The compound according to Item 9, which is
(Item 11)
  R ³ But C ₁ -C ₈ Alkyl, C ₁ -C ₈ Item 11. The compound according to any one of Items 1 to 10, which is haloalkyl or cyclopropyl.
(Clause 12)
  R ³ Item 12. The compound according to Item 11, wherein is methyl or trifluoromethyl.
(Section 13)
  R ⁸ But C ₁ -C ₈ Alkyl or C ₁ -C ₈ Item 13. The compound according to any one of Items 1 to 12, which is haloalkyl.
(Item 14)
  R ⁸ Item 14. The compound according to Item 13, wherein is methyl or trifluoromethyl.
(Section 15)
  R ⁶ 15. The compound according to any one of Items 1 to 14, wherein is —OH.
(Section 16)
  R ⁵ Item 16. The compound according to any one of Items 1 to 15, wherein is cyclohexyl.
(Section 17)
  R ¹ But C ₁ -C ₈ Alkyl or C ₁ -C ₈ Item 17. The compound according to any one of Items 1 to 16, which is haloalkyl.
(Item 18)
  R ¹ Is ethyl or -CHF ₂ Item 17. The compound according to Item 16, wherein
(Section 19)
  Said compound is of formula (Ia):

Having the structure:
  R ¹ Is C ₁ -C ₈ Alkyl or C ₁ -C ₈ Is haloalkyl;
  R ² Is H, or a non-sugar mimetic moiety or a linker-non-sugar mimetic moiety, wherein the non-sugar mimetic moiety is polyethylene glycol, thiazolyl, chromenyl, —C (═O) NH (CH ₂ ) _1-4 NH ₂ , C ₁ -C ₈ Alkyl and -C (= O) OY (where Y is C ₁ -C ₄ Selected from alkyl);
  R ³ Is C ₁ -C ₈ Alkyl, C ₁ -C ₈ Haloalkyl or cyclopropyl;
  R ⁴ Is —OH or —NZ ¹ Z ² (Where Z ¹ And Z ² Are each independently H or C ₁ -C ₈ Is alkyl);
  R ⁷ Is -CH ₂ OH, C ₁ -C ₈ Alkyl, C ₁ -C ₈ Haloalkyl, and
  R ⁸ Is C ₁ -C ₈ Alkyl or C ₁ -C ₈ Haloalkyl,
Item 2. The compound according to Item 1.
(Section 20)
  Item 20. The compound according to Item 19, wherein halo is F.
(Item 21)
  R ¹ Is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ Or -CH ₂ CF ₃ Item 21. The compound according to Item 19 or Item 20, wherein
(Item 22)
  R ³ Is -CH ₃ , -CH ₂ F, -CHF ₂ Or -CF ₃ The compound according to any one of Items 19 to 21 above.
(Item 23)
  R ⁴ Is —OH or —N (CH ₃ ) ₂ Item 23. The compound according to any one of Items 19 to 22 above.
(Section 24)
  R ⁷ Is -CH ₂ OH, -CH ₃ , -CH ₂ F, -CHF ₂ Or -CF ₃ 24. The compound according to any one of Items 19 to 23, wherein
(Claim 25)
  R ⁸ Is -CH ₃ , -CH ₂ F, -CHF ₂ Or -CF ₃ The compound according to any one of Items 19 to 24, wherein:
(Claim 26)
  R ² 26. The compound of any one of clauses 1 to 25, wherein is a linker-non-sugar mimetic moiety and the non-sugar mimetic moiety comprises polyethylene glycol.
(Section 27)
  formula:

Item 27. The compound according to Item 26, wherein n is 1 to 100.
(Item 28)
  Item 28. The compound according to Item 27, wherein n is 4, 8, 12, 16, 20, 24, or 28.
(Item 29)
  formula:

Item 29. The compound according to Item 28, having one of the following:
(Section 30)
  R ² Is a linker-non-sugar mimetic moiety and the compound has the formula:

The compound of claim 1 having one of the following:
(Claim 31)
  The following formula:

Item 15. The compound according to Item 1 or 14, wherein the compound has one of the following.
(Item 32)
  The following formula:

The compound of claim 1 having one of the following:
(Paragraph 33)
  33. A pharmaceutical composition comprising the compound according to any one of items 1 to 32 and a pharmaceutically acceptable excipient.
(Section 34)
  34. A method for treating or preventing metastasis of cancer cells in a subject, comprising administering to the subject the pharmaceutical composition according to Item 33.
(Claim 35)
  A method for treating or preventing metastasis of cancer cells in a subject, comprising: (a) a pharmaceutically acceptable excipient; and (b) binding to E-selectin, 15. A method comprising administering to the subject a pharmaceutical composition comprising an agent capable of competing with the compound of any one of the claims, wherein the agent is an antibody, polypeptide, peptide, or aptamer.
(Claim 36)
  34. A method for inhibiting cancer cells from infiltrating the bone marrow in a subject, comprising administering the pharmaceutical composition according to Item 33 to the subject.
(Paragraph 37)
  The method for inhibiting cancer cells from infiltrating the bone marrow in a subject, the pharmaceutically acceptable excipient and binding to E-selectin according to any one of the above items 1 to 32 17. A method comprising administering to the subject a pharmaceutical composition comprising an agent capable of competing with the described compound and being an antibody, polypeptide, peptide, or aptamer.
(Claim 38)
  A method for inhibiting adhesion of tumor cells expressing an E-selectin ligand to endothelial cells expressing E-selectin, comprising: (a) a pharmaceutically acceptable excipient. And (b) a pharmaceutical composition comprising the compound according to any one of the above items 1 to 32, wherein the compound interacts with E-selectin present on the endothelial cells. Enabling and thereby inhibiting binding of the tumor cells to the endothelial cells.
(Item 39)
  40. The method of paragraph 38, wherein the endothelial cells are present in bone marrow.
(Claim 40)
  A method for treating cancer in a subject, comprising: (a) administering a pharmaceutical composition according to item 33 above to the subject; and (b) (i) chemotherapy and (ii) radiation therapy. Performing at least one of said subject on said subject.
(Claim 41)
  34. A method for treating or preventing thrombosis in a subject, the method comprising administering to the subject the pharmaceutical composition according to Item 33.
(Item 42)
  A method for treating or preventing thrombosis in a subject, wherein (a) a pharmaceutically acceptable excipient and (b) binding to E-selectin are any one of the above items 1 to 32 A method comprising administering to said subject a pharmaceutical composition comprising an agent capable of competing with the compound according to paragraph and being an antibody, polypeptide, peptide, or aptamer.
(Item 43)
  34. A method for enhancing the survival of hematopoietic stem cells in a subject, comprising administering the pharmaceutical composition according to Item 33 to the subject.
(Item 44)
  44. The method of paragraph 43, wherein the subject has received or is scheduled to receive chemotherapy or radiation therapy or both chemotherapy and radiation therapy.
(Claim 45)
  A method for enhancing the survival of hematopoietic stem cells in a subject, wherein (a) a pharmaceutically acceptable excipient and (b) binding to E-selectin are any one of the above items 1 to 32 A method comprising administering to said subject a pharmaceutical composition comprising an agent capable of competing with the compound according to paragraph and being an antibody, polypeptide, peptide, or aptamer.
(Claim 46)
  46. The method of paragraph 45, wherein the subject has received or is scheduled to receive chemotherapy or radiation therapy or both chemotherapy and radiation therapy.
(Item 47)
  33. Use of the compound according to any one of Items 1 to 32 in the manufacture of a medicament for treating or preventing metastasis of cancer cells.
(Section 48)
  35. Use of a compound according to any one of paragraphs 1-32 in the manufacture of a medicament for use in treating cancer in combination with chemotherapy or radiation therapy or both chemotherapy and radiation therapy.
(Item 49)
  33. Use of the compound according to any one of the above items 1 to 32 in the manufacture of a medicament for treating or preventing thrombosis.
(Section 50)
  33. Use of the compound according to any one of items 1 to 32 in the manufacture of a medicament for inhibiting cancer cells from infiltrating the bone marrow.
(Item 51)
  33. Use of the compound according to any one of the above items 1 to 32 in the manufacture of a medicament for inhibiting adhesion of tumor cells expressing an E-selectin ligand to endothelial cells expressing E-selectin.
(Item 52)
  33. Use of the compound according to any one of the above items 1 to 32 in the manufacture of a medicament for enhancing the survival of hematopoietic stem cells.

Claims (15)

formula:

Has, in the formula, n, 2 - 100, a 2～50,2～20 or 2-15, of compound or a pharmaceutically acceptable salt, tautomer, hydrate, Or a solvate. n is, 4,8,12,16,20,24 or 28 A compound or a pharmaceutically acceptable salt, tautomer, hydrate according to claim 1, or a solvate, . The compound is :

In it, a compound or a pharmaceutically acceptable salt, tautomer according to claim 1, hydrates or solvates.   The compound is:

Or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof according to claim 1. The compound is:
Or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof according to claim 1 . 6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof and optionally at least one pharmaceutically acceptable. A pharmaceutical composition comprising:   A composition for treating, reducing, inhibiting or reducing the likelihood of cancer cell metastasis in a subject, comprising the pharmaceutical composition of claim 6.   A composition for inhibiting cancer cells from infiltrating the bone marrow in a subject, comprising the pharmaceutical composition according to claim 6. A composition for inhibiting adhesion of tumor cells expressing an E-selectin ligand to endothelial cells expressing E-selectin, wherein the composition is according to any one of claims 1 to 5. Or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof, wherein the composition interacts with E-selectin present on the endothelial cells. A composition characterized in that it is allowed to act and the binding of the tumor cells to the endothelial cells is inhibited. A composition for inhibiting adhesion of tumor cells expressing an E-selectin ligand to endothelial cells expressing E-selectin, wherein the composition is according to any one of claims 1 to 5. A pharmaceutical composition comprising the described compound or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof and optionally at least one pharmaceutically acceptable excipient. The composition comprising: allowing the compound to interact with E-selectin present on the endothelial cells and inhibiting binding of the tumor cells to the endothelial cells. A composition, characterized.   The composition according to claim 9 or 10, wherein the endothelial cells are present in bone marrow.   A composition for treating cancer in a subject, said composition comprising a pharmaceutical composition according to claim 6, wherein said composition comprises at least (i) chemotherapy and (ii) radiation therapy. A composition, characterized in that it is administered together with one.   A composition for treating, reducing, inhibiting or reducing the likelihood of thrombosis in a subject, comprising the pharmaceutical composition of claim 6.   A composition for enhancing the survival of hematopoietic stem cells in a subject, comprising the pharmaceutical composition according to claim 6.   15. The composition of claim 14, wherein the subject has received or is scheduled to receive chemotherapy or radiation therapy or both chemotherapy and radiation therapy.